{"gene":"IL24","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2001,"finding":"IL-24 (MDA-7) is a secreted protein that functions as the ligand for two heterodimeric type II cytokine receptor complexes: IL-22R1/IL-20R2 and IL-20R1/IL-20R2. Binding to either receptor complex on human keratinocytes or ectopically expressed receptors on baby hamster kidney cells leads to activation of STAT transcription factors.","method":"Ligand-receptor binding assays (saturation kinetics on transfected COS cells), STAT activation assays on keratinocytes and BHK cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding assays with transfected receptor heterodimers, functional STAT activation readout, replicated on endogenous and ectopic receptors","pmids":["11706020"],"is_preprint":false},{"year":2003,"finding":"MDA-7/IL-24-induced cancer-specific apoptosis occurs through JAK/STAT-independent pathways; inhibition of JAK (AG490), general tyrosine kinases (genistein, AG18), or absence of IL-20R/IL-22R expression did not prevent Ad.mda-7-induced apoptosis. Instead, partial inhibition of apoptosis was achieved with the p38 MAPK inhibitor SB203580, implicating p38 MAPK as a mediator of cancer cell killing.","method":"Pharmacological inhibition with selective kinase inhibitors; apoptosis assays in STAT/JAK-deficient cell lines; receptor expression profiling","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal pharmacological inhibitors plus genetic (JAK/STAT-deficient cells), replicated across diverse cancer cell lines","pmids":["12811827"],"is_preprint":false},{"year":2003,"finding":"Ad.mda-7 expression in glioma cells activates p38 and ERK1/2, and radiosensitization of glioma cells by MDA-7/IL-24 requires JNK1/2 signaling; inhibition of JNK1/2 (but not p38) abolished radiosensitization. ERK and PI3K signaling are protective against MDA-7 lethality.","method":"Pharmacological inhibitor studies (JNK inhibitor SP600125, MEK/PI3K inhibitors), colony formation assays, cell cycle analysis","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean pharmacological epistasis with specific inhibitors, single lab","pmids":["14508103"],"is_preprint":false},{"year":2003,"finding":"MDA-7/IL-24 negatively regulates both the beta-catenin and PI3K signaling pathways in breast and lung cancer cells; it redistributes beta-catenin from nucleus to plasma membrane (reducing TCF/LEF transcription), upregulates E-cadherin, APC, GSK-3beta, PTEN, and downregulates FAK, ILK-1, Akt, and PLC-gamma in a tumor cell-specific manner.","method":"Microarray analysis, Western blotting, reporter gene assay (TCF/LEF luciferase), pharmacological PI3K inhibition (wortmannin)","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (microarray, western blot, reporter assay), single lab","pmids":["12907143"],"is_preprint":false},{"year":2004,"finding":"Secreted glycosylated MDA-7/IL-24 protein kills melanoma cells via IL-20 receptor engagement (both type 1 and type 2 IL-20R) through a STAT3-independent, PKR-independent signaling pathway; receptor engagement induces STAT3 phosphorylation and nuclear translocation but the cytotoxic effect operates through a separate pathway involving BAX upregulation.","method":"Neutralizing anti-MDA-7 and anti-receptor antibodies, STAT3 inhibition, receptor expression on melanoma cells, apoptosis assays with recombinant MDA-7 protein","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (neutralizing antibodies, pharmacological inhibitors, receptor knockdown), single lab","pmids":["15564140"],"is_preprint":false},{"year":2004,"finding":"Ad.mda-7 radiosensitizes non-small cell lung cancer cells by suppressing components of the non-homologous end-joining (NHEJ) DNA repair pathway, specifically downregulating Ku70, XRCC4, and DNA ligase IV protein expression; this correlated with impaired DSB rejoining kinetics measured by pulsed-field gel electrophoresis and reduced host-cell reactivation capacity.","method":"Western blotting, pulsed-field gel electrophoresis (DSB rejoining kinetics), host cell reactivation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (protein expression, DSB kinetics, HCR), single lab","pmids":["15273727"],"is_preprint":false},{"year":2004,"finding":"Ectopic MDA-7/IL-24 production inhibits lung cancer cell migration and invasion by downregulating PI3K/AKT, focal adhesion kinase (FAK), and matrix metalloproteinases MMP-2 and MMP-9, and reduces experimental lung metastasis in vivo.","method":"Cell migration and invasion assays in vitro, Western blotting for pathway components, experimental lung metastasis mouse model","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assays combined with in vivo metastasis model, mechanistic pathway characterization by western blot, single lab","pmids":["15093181"],"is_preprint":false},{"year":2004,"finding":"GST-MDA-7 fusion protein radiosensitizes primary human glioma cells through ROS generation and JNK1/2/3 activation, operating via both ROS-dependent and ROS-independent parallel pro-apoptotic pathways; JNK signaling activates BAX and the intrinsic (caspase-9) apoptotic pathway; N-acetyl cysteine (NAC) blocked JNK activation and killing but not BAD/BAX upregulation.","method":"MTT assay, clonogenic survival assay, pan-caspase/specific caspase inhibitors, ROS scavenger (NAC), JNK inhibitor (SP600125), 3D soft agar overlay assays with secretion-deficient MDA-7 mutant","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological agents and genetic tools, secretion-deficient mutant used as control, single lab","pmids":["15197348"],"is_preprint":false},{"year":2005,"finding":"MDA-7/IL-24-induced apoptosis in human ovarian cancer cells involves activation of transcription factors c-Jun and ATF-2, which drive transcription of FasL and Fas; this is accompanied by NF-κB activation and recruitment of FADD and caspase-8. siRNA knockdown of Fas or antibody blockade of FasL abrogated Ad.mda-7-mediated apoptosis. Fas promoter activity was specifically induced by Ad.mda-7.","method":"siRNA knockdown of Fas, FasL neutralizing antibody (NOK-1), promoter-reporter luciferase assay, Western blotting, apoptosis assays (TUNEL, Annexin V)","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — promoter assay, siRNA knockdown, and antibody blockade all converge on Fas-FasL pathway as mechanistically required, multiple orthogonal experiments","pmids":["15833826"],"is_preprint":false},{"year":2005,"finding":"Secreted MDA-7/IL-24 protein suppresses angiogenesis by sensitizing human umbilical vein endothelial cells (HUVECs) to ionizing radiation, reducing bFGF and VEGF levels and microvessel density in tumors, without sensitizing normal lung fibroblasts.","method":"Clonogenic survival assay with conditioned medium from stably transfected MDA-7 cells, in vivo xenograft tumor model with histological analysis (CD31, bFGF, VEGF)","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditioned medium assay plus in vivo confirmation, single lab","pmids":["15194048"],"is_preprint":false},{"year":2005,"finding":"Ad-mda7 kills pancreatic cancer cells via G2/M arrest and apoptosis through regulation of Wnt/PI3K pathway proteins (beta-catenin, APC, GSK-3, JNK, PTEN). Bystander killing of non-transduced pancreatic cancer cells is mediated specifically by secreted MDA-7 protein engaging IL-20 receptors, as shown by neutralizing anti-MDA-7 and anti-IL-20R antibodies.","method":"Cell cycle analysis, Western blotting, neutralizing antibody experiments (anti-MDA-7, anti-IL-20R), apoptosis assays","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway characterization plus antibody-neutralization demonstrates receptor specificity of bystander effect, single lab","pmids":["15851011"],"is_preprint":false},{"year":2006,"finding":"N-glycosylation of MDA-7/IL-24 is dispensable for cancer-specific apoptosis and bystander antitumor activity. A nonglycosylated, nonsecreted MDA-7/IL-24 mutant (signal peptide deleted, three N-glycosylation sites mutated) retained tumor-selective apoptosis, ER localization, JAK/STAT-independent and p38 MAPK-dependent killing, ER stress induction (BiP/GRP78, GRP94, XBP-1, eIF2alpha), and physical interaction with BiP/GRP78.","method":"Site-directed mutagenesis (N-glycosylation sites), adenoviral expression, co-immunoprecipitation (MDA-7 with BiP/GRP78), Western blotting for ER stress markers, apoptosis assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis combined with co-IP and multiple functional readouts in single study; biochemically rigorous","pmids":["17178884"],"is_preprint":false},{"year":2008,"finding":"Intracellular MDA-7/IL-24 protein induces cancer-specific apoptosis by triggering an endoplasmic reticulum (ER) stress response, evidenced by expression of BiP/GRP78, GRP94, GADD153, and phospho-eIF2α, and reactive oxygen species production. Secreted MDA-7/IL-24 protein activates a positive autocrine feedback loop: recombinant MDA-7/IL-24 induces stabilization of endogenous mda-7/IL-24 mRNA (posttranscriptionally, without activating the promoter), requiring de novo protein synthesis, thereby sustaining ER stress and apoptosis.","method":"mRNA stability assays, promoter-reporter assays, protein synthesis inhibition (cycloheximide), ER stress marker Western blotting, ROS measurement, recombinant MDA-7/IL-24 protein treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal experiments (mRNA stabilization, promoter-reporter, protein synthesis inhibitor, ER stress markers, ROS) in single mechanistic study","pmids":["18599461"],"is_preprint":false},{"year":2008,"finding":"GST-MDA-7 kills primary human glioma cells through PERK-dependent ER stress, which activates JNK1-3 leading to BAX activation and mitochondrial dysfunction. PERK-/- cells are resistant to GST-MDA-7 lethality. GST-MDA-7 also induces PERK- and JNK-dependent autophagic vacuolization of LC3-expressing endosomes; knockdown of ATG5 or Beclin-1 reduces lethality. Cathepsin B-dependent cleavage of BID and suppression of BAD/BIM phosphorylation and HSP70 expression also contribute.","method":"PERK-/- cells, JNK inhibitor, caspase-9 dominant-negative, ATG5/Beclin-1 siRNA knockdown, cathepsin inhibitors, HSP70 overexpression, Western blotting, fluorescence microscopy (LC3-GFP)","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deletion (PERK-/-), multiple siRNA knockdowns, and pharmacological inhibitors with convergent mechanistic conclusions, single highly rigorous study","pmids":["18281515"],"is_preprint":false},{"year":2009,"finding":"GST-MDA-7 kills renal carcinoma cells by ceramide-dependent plasma membrane clustering of CD95 (Fas) and association of CD95 with procaspase-8; downstream signaling involves PERK-dependent ER stress activation of JNK-1/2 and p38 MAPK. Knockdown of CD95 abolished PERK phosphorylation by GST-MDA-7, positioning CD95 upstream of PERK in this pathway. Ceramide generation via ceramide synthase-6 and acid sphingomyelinase was required for CD95 clustering.","method":"siRNA knockdown of CD95, ceramide synthase-6, acid sphingomyelinase; dominant negative PERK; caspase-8 inhibitor; short-form c-FLIP overexpression; Western blotting; autophagy assays (ATG5 knockdown)","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple siRNA knockdowns establishing pathway order, dominant-negative PERK, specific protease inhibitors; rigorous epistasis in single mechanistic study","pmids":["19417161"],"is_preprint":false},{"year":2010,"finding":"Ad.mda-7 infection of cancer cells (but not normal cells) causes increased ceramide accumulation via de novo synthesis (serine palmitoyltransferase-dependent) and acid sphingomyelinase (ASMase) activation; ceramide mediates ER stress induction (blocking ceramide synthesis blocks BiP/GRP78, GADD153, phospho-eIF2α induction). Ceramide activates protein phosphatase 2A (PP2A), leading to dephosphorylation of anti-apoptotic BCL-2.","method":"Lipidomic analysis of ceramide species (C16, C24, C24:1), SPT inhibitor myriocin (ISP1), fumonisin B1, ASMase siRNA knockdown, PP2A activity assay, Western blotting for ER stress markers","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct ceramide quantification by lipidomics, enzyme inhibitors, siRNA knockdown, and PP2A activity assay converge on mechanistic conclusion","pmids":["19937735"],"is_preprint":false},{"year":2011,"finding":"In prostate cancer cells, Ad.mda-7 induces early autophagy that switches to apoptosis; MDA-7/IL-24 protein physically interacts with Beclin-1 (potentially inhibiting its autophagy-promoting function), and calpain-mediated cleavage of ATG5 contributes to the autophagy-to-apoptosis switch.","method":"Co-immunoprecipitation (MDA-7/IL-24 with Beclin-1), autophagy and apoptosis markers, calpain inhibitor studies","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP identifies physical interaction with Beclin-1; calpain inhibitor experiments support ATG5 cleavage mechanism; single lab","pmids":["21610321"],"is_preprint":false},{"year":2012,"finding":"MDA-7/IL-24 differentially regulates clusterin (CLU) in prostate cancer cells: Ad.mda-7 decreases soluble CLU (sCLU) and increases nuclear CLU (nCLU), promoting apoptosis and G2/M arrest. MDA-7/IL-24 was identified as a CLU-interacting protein by co-immunoprecipitation in DU-145 cells, and the initial sCLU-MDA-7/IL-24 interaction produces a transient cytoprotective effect.","method":"Co-immunoprecipitation (MDA-7/IL-24 with CLU), stable CLU overexpressing clones, Western blotting, cell viability and apoptosis assays, xenograft mouse models","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP identifies physical interaction; stable cell lines and xenograft validate functional consequences; single lab","pmids":["21732348"],"is_preprint":false},{"year":2013,"finding":"MDA-7/IL-24 induces expression of SARI (suppressor of AP-1, induced by IFN) in diverse cancer cells but not normal cells, and SARI expression is required for mda-7/IL-24-mediated cell death (SARI antisense blocked mda-7/IL-24 antitumor effects). Binding of secreted MDA-7/IL-24 to its cognate receptors (IL-20R1/IL-20R2 or IL-22R/IL-20R2) induces p38 MAPK phosphorylation, leading to GADD gene transcription and apoptosis; p38 MAPK inhibition prevented SARI induction by Ad.mda-7.","method":"SARI antisense knockdown, p38 MAPK inhibitor, receptor-binding studies with recombinant His-MDA-7, Western blotting, cell death assays; ERK1/2 inhibitor reversal in pancreatic cancer cells","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antisense knockdown demonstrates SARI requirement; p38 MAPK inhibitor and His-MDA-7 receptor engagement experiments define pathway; single lab","pmids":["24282278"],"is_preprint":false},{"year":2015,"finding":"IL-24 inhibits lung cancer cell migration and invasion by post-transcriptionally downregulating CXCR4 mRNA (decreasing mRNA half-life by >40%), thereby disrupting the SDF-1/CXCR4 signaling axis and reducing pAKT, pmTOR, pPRAS40, and HIF-1α. Combined IL-24 with CXCR4 inhibitors (AMD3100, SJA5) or CXCR4 siRNA showed enhanced inhibition of tumor cell migration.","method":"Doxycycline-inducible stable IL-24 expression, qRT-PCR mRNA half-life assay, Western blotting for CXCR4 and downstream signaling, flow cytometry, cell migration/invasion assays, luciferase reporter assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible expression system, mRNA stability assay, multiple functional readouts, single lab","pmids":["25775124"],"is_preprint":false},{"year":2016,"finding":"MDA-7/IL-24 downregulates miR-221 and upregulates p27 and PUMA in cancer cells; this effect is ROS-dependent and leads to cell death. MDA-7/IL-24 regulates autophagy through a miR-221/Beclin-1 feedback loop (Beclin-1 identified as a new transcriptional target of miR-221). Overexpression of miR-221 rescues cancer cells from mda-7/IL-24-mediated death.","method":"miRNA profiling, overexpression of miR-221, recombinant His-MDA-7 protein treatment, ROS measurement, Western blotting (p27, PUMA, Beclin-1), xenograft model with miR-221-overexpressing cells","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple approaches (miRNA profiling, gain-of-function rescue, in vivo xenograft), single lab","pmids":["27940575"],"is_preprint":false},{"year":2016,"finding":"mda-7/IL-24 induces caspase-3/9-independent apoptosis in neuroblastoma cells through a pathway involving ATM phosphorylation, γ-H2AX induction, and nuclear translocation of apoptosis-inducing factor (AIF). Inhibition of AIF rescued cells from Ad.5/3-CTV-induced death, while pan-caspase inhibition failed. ATM small-molecule inhibitors blocked γ-H2AX, AIF translocation, and PARP cleavage.","method":"AIF siRNA knockdown, ATM inhibitors, pan-caspase inhibitor (z-VAD), Western blotting (γ-H2AX, phospho-ATM, AIF), nuclear fractionation, in vivo xenograft","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown plus pharmacological ATM inhibitors with convergent results, in vivo validation, single lab","pmids":["27197168"],"is_preprint":false},{"year":2018,"finding":"IL-24 promotes apoptosis in breast cancer cells through cAMP-dependent PKA activation, which is required for IL-24-induced cell death; PKA stimulates p38 MAPK phosphorylation, upregulates Fas/FasL pathway components and death receptor 4, and induces phosphorylation and nuclear import of TP53.","method":"PKA inhibition/activation pharmacological studies, Western blotting (phospho-p38, phospho-TP53, FasL, DR4), cell viability assays, nuclear fractionation","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with multiple readouts; single lab; methods partly inferred from abstract","pmids":["30424508"],"is_preprint":false},{"year":2019,"finding":"MDA-7/IL-24 downregulates DICER (a key miRNA processing enzyme) in multiple cancer cells but not normal cells, through IL-20/IL-22 receptors; this is ROS-dependent and mediated through melanogenesis-associated transcription factor (MITF). DICER overexpression partially rescues cancer cells from mda-7/IL-24-mediated cell death and impedes mda-7/IL-24 inhibition of tumor growth in vivo.","method":"Gain- and loss-of-function studies (DICER overexpression/knockdown), recombinant His-MDA-7 protein, Western blotting (DICER, DROSHA, PASHA, Argonaute), receptor neutralization, ROS measurement, xenograft tumor model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (receptor neutralization, DICER gain/loss-of-function, in vivo validation, MITF pathway), replicated with both adenoviral and recombinant protein delivery","pmids":["30842276"],"is_preprint":false},{"year":2000,"finding":"The mda-7 gene promoter contains functional binding sites for AP-1 (c-Jun) and C/EBP transcription factors; ectopic expression of AP-1/c-Jun or C/EBP enhances mda-7 promoter activity in melanoma cells while a dominant-negative c-Jun (TAM67) does not. Electrophoretic mobility shift assays (EMSA) confirmed binding of nuclear proteins from terminally differentiated melanoma cells to AP-1 and C/EBP consensus sites in the mda-7 promoter.","method":"Luciferase reporter assay (mda-7 promoter-luciferase), EMSA with nuclear extracts, Western blotting (cJun, C/EBP-beta), dominant-negative c-Jun overexpression","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay, EMSA, and dominant-negative mutant converge on mechanism; single lab","pmids":["10942517"],"is_preprint":false},{"year":2001,"finding":"FISP (murine IL-24 ortholog) is selectively expressed and secreted by Th2 cells; its expression during Th2 differentiation requires two signals: TCR signaling involving protein kinase C activation, and STAT6-dependent IL-4 receptor signaling.","method":"Differential gene expression during Th1/Th2 differentiation, PKC activation/inhibition, STAT6-deficient cells, secretion assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (STAT6-deficient) and pharmacological dissection of signaling requirements; single lab","pmids":["11342597"],"is_preprint":false},{"year":2020,"finding":"IL-17A triggers a Th17 cell-intrinsic autocrine negative feedback loop: IL-17A binds its receptor on Th17 cells, activates NF-κB, which induces IL-24 expression; IL-24 in turn represses the Th17 cytokine program (GM-CSF, IL-17F). In vivo, IL-24 treatment ameliorated Th17-induced EAU, while IL-24 silencing in Th17 cells enhanced disease.","method":"IL-17A loss-of-function in Th17 cells, mechanistic in vitro NF-κB activation studies, IL-24 silencing in Th17 cells, IL-24 treatment of EAU mouse model, cytokine measurements","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection with genetic knockdown, pharmacological NF-κB studies, in vivo disease model, replicated in human Th17 cells; high-quality journal","pmids":["32673565"],"is_preprint":false},{"year":2022,"finding":"IL-24 protein accumulates in the cytosol under conditions of proteasome dysfunction (when ER-associated degradation is blocked), and cytoplasmic IL-24 activates PKR (protein kinase R), which serves as an innate immune sensor for proteotoxic stress. PKR activation by cytoplasmic IL-24 drives NF-κB and type I IFN signaling; PKR also phosphorylates eIF2α to limit new protein translation. Blocking IL-24 egress into the cytosol (by inhibiting ERAD) suppressed PKR activation and downstream inflammatory signaling.","method":"PKR genetic deletion in vitro and in vivo (PKR-deficient mice), proteasome inhibitor-induced inflammatory models, ERAD inhibition to block cytoplasmic IL-24 accumulation, eIF2α phosphorylation assays, patient cells from PRAAS","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deletion of PKR in vitro and in vivo, ERAD inhibition to block IL-24 cytosol accumulation, multiple cell types including patient samples, mechanistically rigorous","pmids":["35148201"],"is_preprint":false},{"year":2022,"finding":"In Th17 cells, IL-24 is recruited to the inner mitochondrial membrane where it interacts with NADH dehydrogenase (ubiquinone) 1 α subcomplex subunit 13 (GRIM19/NDUFA13), a complex I respiratory chain component. Together, IL-24 and GRIM19 promote accumulation of STAT3 in the mitochondrial compartment, limiting STAT3 nuclear deflections and promoting IL-10 production to restrain Th17 pathogenicity. This function is independent of IL-24 cell surface receptor signaling.","method":"Mitochondrial fractionation, co-immunoprecipitation (IL-24 with GRIM19), STAT3 mitochondrial localization assays, receptor-independent signaling experiments, EAU model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP demonstrating physical interaction, mitochondrial fractionation showing localization, receptor-independence established, functional consequence (STAT3 compartmentalization, IL-10) demonstrated","pmids":["35819408"],"is_preprint":false},{"year":2004,"finding":"A novel splice variant of mda-7/IL-24 (mda-7s), encoding a 63-residue 12 kDa protein lacking exons 3 and 5, co-precipitates full-length MDA-7 and reduces secretion of co-transfected MDA-7 protein.","method":"Co-immunoprecipitation (mda-7s with full-length MDA-7), secretion assays, RT-PCR expression analysis","journal":"The Journal of investigative dermatology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP experiment; functional significance of interaction not elaborated; single lab","pmids":["15304100"],"is_preprint":false},{"year":2020,"finding":"IL-24 deficiency protects mice from bleomycin-induced pulmonary fibrosis; mechanistically, IL-24 synergizes with IL-4 to promote macrophage M2 polarization by suppressing IL-4-induced SOCS1 and SOCS3 expression, thereby enhancing STAT6/PPARγ signaling.","method":"IL-24 knockout mice, bleomycin fibrosis model, macrophage M2 polarization assays, Western blotting (SOCS1, SOCS3, STAT6, PPARγ), cytokine quantification (TGF-β1)","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout model, mechanistic pathway dissection (SOCS1/3-STAT6/PPARγ), in vivo and in vitro convergent evidence, single lab with multiple orthogonal methods","pmids":["33144678"],"is_preprint":false},{"year":2006,"finding":"In CLL B-cells, MDA-7/IL-24 activates p38 MAPK, and this activation is required for CLL cell survival; siRNA knockdown of mda-7/IL-24 specifically inhibited p38 MAPK phosphorylation and increased spontaneous apoptosis three-fold. Recombinant IL-24 could re-induce p38 MAPK phosphorylation.","method":"siRNA knockdown of mda-7/IL-24, p38 MAPK pharmacological inhibitor (SB203580), recombinant IL-24 protein treatment, Western blotting, apoptosis assays","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown plus pharmacological inhibitor plus recombinant protein rescue; single lab","pmids":["16408101"],"is_preprint":false},{"year":2018,"finding":"Recombinant MDA-7/IL-24 protein inhibits prostate cancer bone metastasis by both selectively killing prostate cancer cells and inhibiting osteoclast differentiation. Gain- and loss-of-function studies show that the Akt and Mcl-1 prosurvival pathways are critically required for anti-bone metastatic activity of MDA-7/IL-24.","method":"Bone metastasis experimental model, gain/loss-of-function genetic approaches (Akt, Mcl-1), Mcl-1 small-molecule inhibitor, in vivo femur metastasis quantification, Western blotting","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic gain/loss-of-function plus in vivo model; single lab","pmids":["29934341"],"is_preprint":false}],"current_model":"IL-24 (MDA-7) is a secreted IL-10-family cytokine that signals through two heterodimeric receptors (IL-22R1/IL-20R2 and IL-20R1/IL-20R2) to activate STAT transcription factors; at supra-physiological levels it induces cancer-selective apoptosis and toxic autophagy by triggering endoplasmic reticulum stress (via PERK/eIF2α phosphorylation), ceramide generation (through de novo synthesis and acid sphingomyelinase), and activation of p38 MAPK and JNK signaling, while in immune contexts it operates through an autocrine loop in Th17 cells—recruiting to the inner mitochondrial membrane to interact with GRIM19 and promote mitochondrial STAT3 accumulation—and also acts as a cytoplasmic danger-associated molecular pattern that activates PKR under proteotoxic stress conditions."},"narrative":{"mechanistic_narrative":"IL-24 (MDA-7) is a secreted IL-10-family cytokine that signals through two heterodimeric type II receptor complexes (IL-22R1/IL-20R2 and IL-20R1/IL-20R2) to activate STAT transcription factors on keratinocytes and other targets [PMID:11706020]. Its best-characterized role is as a cancer-selective cytotoxic effector: at high intracellular levels IL-24 localizes to the endoplasmic reticulum and triggers a tumor-restricted ER stress program (BiP/GRP78, GRP94, GADD153, phospho-eIF2α) through physical interaction with the chaperone BiP/GRP78, killing cancer but not normal cells via JAK/STAT-independent, p38 MAPK-dependent signaling [PMID:17178884, PMID:18599461]. This lethality proceeds through PERK-dependent ER stress that activates JNK and BAX-driven mitochondrial dysfunction and a coupled toxic autophagy program requiring ATG5 and Beclin-1 [PMID:18281515], with de novo and acid-sphingomyelinase-driven ceramide generation upstream—ceramide clusters CD95/Fas, activates PP2A to dephosphorylate BCL-2, and feeds the ER stress response [PMID:19417161, PMID:19937735]. Downstream death is executed through transcriptional induction of the Fas/FasL axis via c-Jun/ATF-2 [PMID:15833826] and the IFN-inducible mediator SARI [PMID:24282278], while IL-24 also represses pro-survival and metastatic signaling (β-catenin, PI3K/AKT, FAK, MMPs, CXCR4) and suppresses NHEJ repair to radiosensitize tumors [PMID:12907143, PMID:15273727, PMID:25775124]. Distinct from these cytotoxic functions, IL-24 acts as an intrinsic immune regulator: in Th17 cells it is induced by IL-17A/NF-κB as an autocrine brake on the pathogenic cytokine program [PMID:32673565] and, independent of surface receptor signaling, is recruited to the inner mitochondrial membrane where it binds GRIM19/NDUFA13 to promote mitochondrial STAT3 retention and IL-10 production [PMID:35819408]. Under proteotoxic stress, cytosolic IL-24 accumulating after blocked ER-associated degradation activates PKR, driving eIF2α phosphorylation, NF-κB, and type I IFN signaling as an innate sensor of proteostasis collapse [PMID:35148201].","teleology":[{"year":2000,"claim":"Established how the mda-7/IL-24 gene itself is transcriptionally controlled, identifying the regulatory inputs that drive its expression in differentiating melanoma cells.","evidence":"Promoter-luciferase, EMSA, and dominant-negative c-Jun in melanoma cells","pmids":["10942517"],"confidence":"Medium","gaps":["Does not address protein function downstream of expression","Restricted to melanoma context"]},{"year":2001,"claim":"Defined IL-24 as a bona fide cytokine ligand by showing it binds two heterodimeric type II receptor complexes and activates STATs, placing it in canonical cytokine signaling.","evidence":"Ligand-receptor binding assays and STAT activation on keratinocytes and transfected cells","pmids":["11706020"],"confidence":"High","gaps":["Does not explain cancer-selective cytotoxicity","Physiological target tissues incompletely mapped"]},{"year":2001,"claim":"Showed the murine ortholog (FISP) is a Th2-restricted secreted product requiring TCR/PKC and STAT6 signals, giving IL-24 an early immune-cell identity beyond epithelial signaling.","evidence":"Th1/Th2 differentiation profiling, PKC modulation, STAT6-deficient cells","pmids":["11342597"],"confidence":"Medium","gaps":["Functional consequence of Th2 secretion not defined","Ortholog data may not fully translate to human"]},{"year":2003,"claim":"Decoupled IL-24's cytokine receptor/STAT signaling from its tumor-killing activity, demonstrating apoptosis proceeds through JAK/STAT-independent, p38 MAPK-dependent routes.","evidence":"Kinase inhibitors and JAK/STAT-deficient cancer lines with apoptosis readouts","pmids":["12811827"],"confidence":"High","gaps":["Did not identify the receptor-independent intracellular trigger","p38 only partially required"]},{"year":2003,"claim":"Linked IL-24 to suppression of oncogenic signaling, showing it down-regulates β-catenin/TCF and PI3K/AKT outputs in a tumor-selective manner.","evidence":"Microarray, Western blot, TCF/LEF reporter, PI3K inhibition in breast/lung cells","pmids":["12907143"],"confidence":"Medium","gaps":["Mechanism linking IL-24 to pathway suppression unclear","Single lab"]},{"year":2004,"claim":"Began assembling the death machinery downstream of IL-24, identifying ROS- and JNK-dependent BAX activation and the intrinsic caspase-9 pathway, and showing migration/invasion suppression via PI3K/FAK/MMP down-regulation.","evidence":"ROS scavengers, JNK inhibitors, caspase inhibitors, migration/invasion and in vivo metastasis assays","pmids":["15197348","15093181","15564140"],"confidence":"Medium","gaps":["Upstream ER signal not yet defined","Parallel ROS-dependent and -independent arms not fully resolved"]},{"year":2004,"claim":"Connected IL-24 to radiosensitization by showing it suppresses NHEJ DNA repair components and impairs double-strand break rejoining.","evidence":"Western blot, pulsed-field gel electrophoresis, host-cell reactivation in NSCLC","pmids":["15273727"],"confidence":"Medium","gaps":["Mechanism of Ku70/XRCC4/ligase IV down-regulation unknown","Single lab"]},{"year":2005,"claim":"Identified the Fas/FasL death-receptor axis as a transcriptional effector of IL-24 killing, driven by c-Jun/ATF-2 and NF-κB.","evidence":"Fas siRNA, FasL neutralizing antibody, promoter-reporter, apoptosis assays in ovarian cancer","pmids":["15833826"],"confidence":"High","gaps":["Link to upstream ER/ceramide signaling not yet drawn","Cell-type generality untested here"]},{"year":2005,"claim":"Established the secreted, bystander-acting nature of IL-24 toxicity, showing conditioned medium sensitizes endothelium and kills non-transduced tumor cells through IL-20 receptor engagement.","evidence":"Conditioned medium clonogenic assays, neutralizing anti-MDA-7/anti-IL-20R antibodies, xenograft histology","pmids":["15194048","15851011"],"confidence":"Medium","gaps":["Reconciliation of receptor-dependent bystander killing with receptor-independent intracellular killing unresolved","Single lab"]},{"year":2006,"claim":"Revealed a context-dependent pro-survival role: in CLL B-cells endogenous IL-24 sustains p38 MAPK signaling required for survival, contrasting with its cytotoxic action in solid tumors.","evidence":"IL-24 siRNA knockdown, SB203580, recombinant IL-24 rescue, apoptosis assays","pmids":["16408101"],"confidence":"Medium","gaps":["Molecular basis for opposite p38 outcomes across cell types unexplained","Single lab"]},{"year":2006,"claim":"Separated IL-24's intracellular cytotoxic function from secretion and glycosylation, showing a nonsecreted, nonglycosylated mutant retains ER localization, BiP/GRP78 binding, and tumor-selective ER-stress killing.","evidence":"Site-directed mutagenesis, co-IP with BiP/GRP78, ER stress marker Western blots, apoptosis assays","pmids":["17178884"],"confidence":"High","gaps":["Does not explain why ER stress is tumor-selective","BiP/GRP78 interaction's mechanistic consequence not fully defined"]},{"year":2008,"claim":"Built the core ER-stress death pathway, placing PERK upstream of JNK/BAX and a coupled toxic autophagy program, and uncovering an autocrine loop stabilizing IL-24 mRNA to sustain the response.","evidence":"PERK-/- cells, ATG5/Beclin-1 siRNA, mRNA stability and protein-synthesis inhibition, ROS measurement in glioma and other cancers","pmids":["18281515","18599461"],"confidence":"High","gaps":["Trigger of initial ER stress not yet identified","Autophagy-apoptosis switch mechanism incomplete"]},{"year":2009,"claim":"Inserted ceramide and CD95 clustering upstream of ER stress, ordering CD95 above PERK in the killing cascade.","evidence":"siRNA of CD95, ceramide synthase-6, ASMase; dominant-negative PERK; caspase-8 inhibitor in renal carcinoma","pmids":["19417161"],"confidence":"High","gaps":["How IL-24 initiates ceramide generation unresolved","Single lab"]},{"year":2010,"claim":"Defined the lipid trigger of IL-24 lethality, showing tumor-selective ceramide accumulation via de novo synthesis and ASMase drives ER stress and PP2A-mediated BCL-2 dephosphorylation.","evidence":"Lipidomics, SPT/ceramide synthase inhibitors, ASMase siRNA, PP2A activity assay","pmids":["19937735"],"confidence":"High","gaps":["Molecular sensor connecting IL-24 to ceramide enzymes unidentified","Tumor-selectivity basis unexplained"]},{"year":2011,"claim":"Identified Beclin-1 as a direct IL-24 binding partner and a calpain/ATG5 mechanism governing the autophagy-to-apoptosis switch.","evidence":"Co-IP of IL-24 with Beclin-1, calpain inhibitors, autophagy/apoptosis markers in prostate cancer","pmids":["21610321"],"confidence":"Medium","gaps":["Functional consequence of Beclin-1 binding inferred, not directly demonstrated","Single Co-IP"]},{"year":2012,"claim":"Expanded IL-24's interactome to clusterin, distinguishing a transient sCLU-mediated cytoprotection from nCLU-driven apoptosis.","evidence":"Co-IP of IL-24 with CLU, stable CLU clones, xenografts in prostate cancer","pmids":["21732348"],"confidence":"Medium","gaps":["Direct vs indirect interaction not fully resolved","Single lab"]},{"year":2013,"claim":"Identified SARI as a required transcriptional effector downstream of receptor-engaged, p38-driven IL-24 signaling, linking the cytokine arm to cancer-selective death.","evidence":"SARI antisense, p38 inhibitor, His-MDA-7 receptor binding in diverse cancers","pmids":["24282278"],"confidence":"Medium","gaps":["How SARI executes death not detailed","Single lab"]},{"year":2015,"claim":"Extended IL-24's anti-metastatic action by showing post-transcriptional CXCR4 mRNA destabilization disrupts the SDF-1/CXCR4 axis and downstream AKT/mTOR/HIF-1α signaling.","evidence":"Inducible IL-24 expression, mRNA half-life qRT-PCR, migration/invasion assays in lung cancer","pmids":["25775124"],"confidence":"Medium","gaps":["Mechanism of mRNA destabilization unidentified","Single lab"]},{"year":2016,"claim":"Linked IL-24 to miRNA control, showing ROS-dependent miR-221 down-regulation derepresses p27/PUMA and a miR-221/Beclin-1 feedback loop regulates autophagy.","evidence":"miRNA profiling, miR-221 overexpression rescue, His-MDA-7, xenografts","pmids":["27940575"],"confidence":"Medium","gaps":["Connection to core ER-stress pathway unclear","Single lab"]},{"year":2016,"claim":"Uncovered a caspase-independent death route via ATM activation, γ-H2AX, and nuclear AIF translocation in neuroblastoma.","evidence":"AIF siRNA, ATM inhibitors, pan-caspase inhibitor, nuclear fractionation, xenograft","pmids":["27197168"],"confidence":"Medium","gaps":["Trigger of ATM activation by IL-24 unknown","Single lab"]},{"year":2018,"claim":"Added cAMP/PKA as an upstream activator coupling IL-24 to p38, Fas/FasL/DR4, and TP53 nuclear import in breast cancer, and defined Akt/Mcl-1 dependence of anti-bone-metastatic activity.","evidence":"PKA pharmacology, Western blots, nuclear fractionation; gain/loss-of-function of Akt/Mcl-1 in bone metastasis model","pmids":["30424508","29934341"],"confidence":"Medium","gaps":["How IL-24 raises cAMP/PKA not defined","Context-dependent pro-survival vs pro-death roles unreconciled"]},{"year":2019,"claim":"Connected IL-24 to global miRNA biogenesis, showing receptor- and ROS/MITF-dependent down-regulation of DICER as a tumor-selective death mechanism.","evidence":"Receptor neutralization, DICER gain/loss-of-function, His-MDA-7, xenografts","pmids":["30842276"],"confidence":"High","gaps":["Link between DICER loss and apoptosis execution incomplete","MITF regulation mechanism partial"]},{"year":2020,"claim":"Revealed a physiological immunoregulatory function: IL-17A/NF-κB induces IL-24 in Th17 cells as an autocrine brake that represses the pathogenic Th17 cytokine program.","evidence":"IL-17A loss-of-function, NF-κB studies, IL-24 silencing, EAU model in mouse and human Th17 cells","pmids":["32673565"],"confidence":"High","gaps":["Mechanism by which IL-24 represses Th17 cytokines not fully defined here","Receptor dependence of this loop not detailed"]},{"year":2020,"claim":"Defined a pro-fibrotic role through macrophage polarization, where IL-24 synergizes with IL-4 by suppressing SOCS1/3 to enhance STAT6/PPARγ-driven M2 polarization.","evidence":"IL-24 knockout mice, bleomycin fibrosis model, M2 polarization assays, SOCS/STAT6/PPARγ Western blots","pmids":["33144678"],"confidence":"High","gaps":["Receptor mediating macrophage effect not specified","Relationship to cytotoxic functions unaddressed"]},{"year":2022,"claim":"Established receptor-independent intracellular roles for IL-24: as a cytosolic DAMP activating PKR under proteotoxic stress, and as an inner-mitochondrial-membrane GRIM19 partner directing mitochondrial STAT3 and IL-10 in Th17 cells.","evidence":"PKR-deficient mice, ERAD inhibition, PRAAS patient cells; mitochondrial fractionation and co-IP with GRIM19/NDUFA13 in Th17 cells","pmids":["35148201","35819408"],"confidence":"High","gaps":["Mechanism of IL-24 cytosol egress incompletely defined","How a single protein partitions between secreted, ER, mitochondrial, and cytosolic roles unresolved"]},{"year":null,"claim":"It remains unresolved how IL-24's tumor-selective intracellular ceramide/ER-stress death program, its receptor-dependent STAT cytokine signaling, and its receptor-independent mitochondrial/cytosolic immune functions are mechanistically coordinated, and what determines its opposite pro- vs anti-survival outcomes across cell types.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking secreted, ER, mitochondrial, and cytosolic IL-24 pools","Basis of cancer-cell selectivity for ceramide/ER stress unidentified","Determinants of pro-survival (CLL) vs pro-death (solid tumor) responses unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,4,18,23]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[11,14,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11,16,28]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[11,12,13]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,4,10]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[28]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[27]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8,13,14,21]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[12,13,15,27]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[26,27,28,30]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,18]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[13,16,20]}],"complexes":[],"partners":["HSPA5","BECN1","CLU","NDUFA13","EIF2AK2","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13007","full_name":"Interleukin-24","aliases":["Melanoma differentiation-associated gene 7 protein","MDA-7","Suppression of tumorigenicity 16 protein"],"length_aa":206,"mass_kda":23.8,"function":"Multifunctional cytokine mainly produced by T-cells that plays a regulatory role in immune response, tissue homeostasis, host defense, and oncogenesis (PubMed:25168428, PubMed:27687232). Possesses antiviral functions and induces the type I interferon response during influenza infection (PubMed:27687232). Signals through two receptor complexes IL20RA/IL20RB or IL20RB/IL22RA1 (PubMed:11706020, PubMed:30111632). In turn, stimulates the JAK1-STAT3 and MAPK pathways and promotes the secretion of pro-inflammatory mediators including IL8 and MMP1 (PubMed:25168428). Intracellularly, maintains endoplasmic reticulum homeostasis by restricting the eIF2alpha-CHOP pathway-mediated stress signal (By similarity). In addition, acts as a quality control mechanism for the ubiquitin proteasome system by alerting the cell to proteasome dysfunction through activation of PKR/EIF2AK2 (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q13007/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL24","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL24","total_profiled":1310},"omim":[{"mim_id":"607900","title":"FERM DOMAIN-CONTAINING KINDLIN 1; FERMT1","url":"https://www.omim.org/entry/607900"},{"mim_id":"605621","title":"INTERLEUKIN 20 RECEPTOR, BETA; IL20RB","url":"https://www.omim.org/entry/605621"},{"mim_id":"605620","title":"INTERLEUKIN 20 RECEPTOR, ALPHA; IL20RA","url":"https://www.omim.org/entry/605620"},{"mim_id":"605457","title":"INTERLEUKIN 22 RECEPTOR, ALPHA-1; IL22RA1","url":"https://www.omim.org/entry/605457"},{"mim_id":"604136","title":"INTERLEUKIN 24; IL24","url":"https://www.omim.org/entry/604136"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":5.5},{"tissue":"urinary bladder","ntpm":13.5}],"url":"https://www.proteinatlas.org/search/IL24"},"hgnc":{"alias_symbol":["mda-7","IL10B","Mob-5","C49A","FISP","IL-24"],"prev_symbol":["ST16"]},"alphafold":{"accession":"Q13007","domains":[{"cath_id":"1.20.1250.10","chopping":"54-206","consensus_level":"high","plddt":93.5907,"start":54,"end":206}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13007","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13007-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13007-F1-predicted_aligned_error_v6.png","plddt_mean":83.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL24","jax_strain_url":"https://www.jax.org/strain/search?query=IL24"},"sequence":{"accession":"Q13007","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13007.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13007/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13007"}},"corpus_meta":[{"pmid":"8799171","id":"PMC_8799171","title":"The 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functions as the ligand for two heterodimeric type II cytokine receptor complexes: IL-22R1/IL-20R2 and IL-20R1/IL-20R2. Binding to either receptor complex on human keratinocytes or ectopically expressed receptors on baby hamster kidney cells leads to activation of STAT transcription factors.\",\n      \"method\": \"Ligand-receptor binding assays (saturation kinetics on transfected COS cells), STAT activation assays on keratinocytes and BHK cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding assays with transfected receptor heterodimers, functional STAT activation readout, replicated on endogenous and ectopic receptors\",\n      \"pmids\": [\"11706020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MDA-7/IL-24-induced cancer-specific apoptosis occurs through JAK/STAT-independent pathways; inhibition of JAK (AG490), general tyrosine kinases (genistein, AG18), or absence of IL-20R/IL-22R expression did not prevent Ad.mda-7-induced apoptosis. Instead, partial inhibition of apoptosis was achieved with the p38 MAPK inhibitor SB203580, implicating p38 MAPK as a mediator of cancer cell killing.\",\n      \"method\": \"Pharmacological inhibition with selective kinase inhibitors; apoptosis assays in STAT/JAK-deficient cell lines; receptor expression profiling\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal pharmacological inhibitors plus genetic (JAK/STAT-deficient cells), replicated across diverse cancer cell lines\",\n      \"pmids\": [\"12811827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Ad.mda-7 expression in glioma cells activates p38 and ERK1/2, and radiosensitization of glioma cells by MDA-7/IL-24 requires JNK1/2 signaling; inhibition of JNK1/2 (but not p38) abolished radiosensitization. ERK and PI3K signaling are protective against MDA-7 lethality.\",\n      \"method\": \"Pharmacological inhibitor studies (JNK inhibitor SP600125, MEK/PI3K inhibitors), colony formation assays, cell cycle analysis\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean pharmacological epistasis with specific inhibitors, single lab\",\n      \"pmids\": [\"14508103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MDA-7/IL-24 negatively regulates both the beta-catenin and PI3K signaling pathways in breast and lung cancer cells; it redistributes beta-catenin from nucleus to plasma membrane (reducing TCF/LEF transcription), upregulates E-cadherin, APC, GSK-3beta, PTEN, and downregulates FAK, ILK-1, Akt, and PLC-gamma in a tumor cell-specific manner.\",\n      \"method\": \"Microarray analysis, Western blotting, reporter gene assay (TCF/LEF luciferase), pharmacological PI3K inhibition (wortmannin)\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (microarray, western blot, reporter assay), single lab\",\n      \"pmids\": [\"12907143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Secreted glycosylated MDA-7/IL-24 protein kills melanoma cells via IL-20 receptor engagement (both type 1 and type 2 IL-20R) through a STAT3-independent, PKR-independent signaling pathway; receptor engagement induces STAT3 phosphorylation and nuclear translocation but the cytotoxic effect operates through a separate pathway involving BAX upregulation.\",\n      \"method\": \"Neutralizing anti-MDA-7 and anti-receptor antibodies, STAT3 inhibition, receptor expression on melanoma cells, apoptosis assays with recombinant MDA-7 protein\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (neutralizing antibodies, pharmacological inhibitors, receptor knockdown), single lab\",\n      \"pmids\": [\"15564140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ad.mda-7 radiosensitizes non-small cell lung cancer cells by suppressing components of the non-homologous end-joining (NHEJ) DNA repair pathway, specifically downregulating Ku70, XRCC4, and DNA ligase IV protein expression; this correlated with impaired DSB rejoining kinetics measured by pulsed-field gel electrophoresis and reduced host-cell reactivation capacity.\",\n      \"method\": \"Western blotting, pulsed-field gel electrophoresis (DSB rejoining kinetics), host cell reactivation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (protein expression, DSB kinetics, HCR), single lab\",\n      \"pmids\": [\"15273727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ectopic MDA-7/IL-24 production inhibits lung cancer cell migration and invasion by downregulating PI3K/AKT, focal adhesion kinase (FAK), and matrix metalloproteinases MMP-2 and MMP-9, and reduces experimental lung metastasis in vivo.\",\n      \"method\": \"Cell migration and invasion assays in vitro, Western blotting for pathway components, experimental lung metastasis mouse model\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assays combined with in vivo metastasis model, mechanistic pathway characterization by western blot, single lab\",\n      \"pmids\": [\"15093181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"GST-MDA-7 fusion protein radiosensitizes primary human glioma cells through ROS generation and JNK1/2/3 activation, operating via both ROS-dependent and ROS-independent parallel pro-apoptotic pathways; JNK signaling activates BAX and the intrinsic (caspase-9) apoptotic pathway; N-acetyl cysteine (NAC) blocked JNK activation and killing but not BAD/BAX upregulation.\",\n      \"method\": \"MTT assay, clonogenic survival assay, pan-caspase/specific caspase inhibitors, ROS scavenger (NAC), JNK inhibitor (SP600125), 3D soft agar overlay assays with secretion-deficient MDA-7 mutant\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological agents and genetic tools, secretion-deficient mutant used as control, single lab\",\n      \"pmids\": [\"15197348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MDA-7/IL-24-induced apoptosis in human ovarian cancer cells involves activation of transcription factors c-Jun and ATF-2, which drive transcription of FasL and Fas; this is accompanied by NF-κB activation and recruitment of FADD and caspase-8. siRNA knockdown of Fas or antibody blockade of FasL abrogated Ad.mda-7-mediated apoptosis. Fas promoter activity was specifically induced by Ad.mda-7.\",\n      \"method\": \"siRNA knockdown of Fas, FasL neutralizing antibody (NOK-1), promoter-reporter luciferase assay, Western blotting, apoptosis assays (TUNEL, Annexin V)\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — promoter assay, siRNA knockdown, and antibody blockade all converge on Fas-FasL pathway as mechanistically required, multiple orthogonal experiments\",\n      \"pmids\": [\"15833826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Secreted MDA-7/IL-24 protein suppresses angiogenesis by sensitizing human umbilical vein endothelial cells (HUVECs) to ionizing radiation, reducing bFGF and VEGF levels and microvessel density in tumors, without sensitizing normal lung fibroblasts.\",\n      \"method\": \"Clonogenic survival assay with conditioned medium from stably transfected MDA-7 cells, in vivo xenograft tumor model with histological analysis (CD31, bFGF, VEGF)\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditioned medium assay plus in vivo confirmation, single lab\",\n      \"pmids\": [\"15194048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ad-mda7 kills pancreatic cancer cells via G2/M arrest and apoptosis through regulation of Wnt/PI3K pathway proteins (beta-catenin, APC, GSK-3, JNK, PTEN). Bystander killing of non-transduced pancreatic cancer cells is mediated specifically by secreted MDA-7 protein engaging IL-20 receptors, as shown by neutralizing anti-MDA-7 and anti-IL-20R antibodies.\",\n      \"method\": \"Cell cycle analysis, Western blotting, neutralizing antibody experiments (anti-MDA-7, anti-IL-20R), apoptosis assays\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway characterization plus antibody-neutralization demonstrates receptor specificity of bystander effect, single lab\",\n      \"pmids\": [\"15851011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"N-glycosylation of MDA-7/IL-24 is dispensable for cancer-specific apoptosis and bystander antitumor activity. A nonglycosylated, nonsecreted MDA-7/IL-24 mutant (signal peptide deleted, three N-glycosylation sites mutated) retained tumor-selective apoptosis, ER localization, JAK/STAT-independent and p38 MAPK-dependent killing, ER stress induction (BiP/GRP78, GRP94, XBP-1, eIF2alpha), and physical interaction with BiP/GRP78.\",\n      \"method\": \"Site-directed mutagenesis (N-glycosylation sites), adenoviral expression, co-immunoprecipitation (MDA-7 with BiP/GRP78), Western blotting for ER stress markers, apoptosis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis combined with co-IP and multiple functional readouts in single study; biochemically rigorous\",\n      \"pmids\": [\"17178884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Intracellular MDA-7/IL-24 protein induces cancer-specific apoptosis by triggering an endoplasmic reticulum (ER) stress response, evidenced by expression of BiP/GRP78, GRP94, GADD153, and phospho-eIF2α, and reactive oxygen species production. Secreted MDA-7/IL-24 protein activates a positive autocrine feedback loop: recombinant MDA-7/IL-24 induces stabilization of endogenous mda-7/IL-24 mRNA (posttranscriptionally, without activating the promoter), requiring de novo protein synthesis, thereby sustaining ER stress and apoptosis.\",\n      \"method\": \"mRNA stability assays, promoter-reporter assays, protein synthesis inhibition (cycloheximide), ER stress marker Western blotting, ROS measurement, recombinant MDA-7/IL-24 protein treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal experiments (mRNA stabilization, promoter-reporter, protein synthesis inhibitor, ER stress markers, ROS) in single mechanistic study\",\n      \"pmids\": [\"18599461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GST-MDA-7 kills primary human glioma cells through PERK-dependent ER stress, which activates JNK1-3 leading to BAX activation and mitochondrial dysfunction. PERK-/- cells are resistant to GST-MDA-7 lethality. GST-MDA-7 also induces PERK- and JNK-dependent autophagic vacuolization of LC3-expressing endosomes; knockdown of ATG5 or Beclin-1 reduces lethality. Cathepsin B-dependent cleavage of BID and suppression of BAD/BIM phosphorylation and HSP70 expression also contribute.\",\n      \"method\": \"PERK-/- cells, JNK inhibitor, caspase-9 dominant-negative, ATG5/Beclin-1 siRNA knockdown, cathepsin inhibitors, HSP70 overexpression, Western blotting, fluorescence microscopy (LC3-GFP)\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deletion (PERK-/-), multiple siRNA knockdowns, and pharmacological inhibitors with convergent mechanistic conclusions, single highly rigorous study\",\n      \"pmids\": [\"18281515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GST-MDA-7 kills renal carcinoma cells by ceramide-dependent plasma membrane clustering of CD95 (Fas) and association of CD95 with procaspase-8; downstream signaling involves PERK-dependent ER stress activation of JNK-1/2 and p38 MAPK. Knockdown of CD95 abolished PERK phosphorylation by GST-MDA-7, positioning CD95 upstream of PERK in this pathway. Ceramide generation via ceramide synthase-6 and acid sphingomyelinase was required for CD95 clustering.\",\n      \"method\": \"siRNA knockdown of CD95, ceramide synthase-6, acid sphingomyelinase; dominant negative PERK; caspase-8 inhibitor; short-form c-FLIP overexpression; Western blotting; autophagy assays (ATG5 knockdown)\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple siRNA knockdowns establishing pathway order, dominant-negative PERK, specific protease inhibitors; rigorous epistasis in single mechanistic study\",\n      \"pmids\": [\"19417161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ad.mda-7 infection of cancer cells (but not normal cells) causes increased ceramide accumulation via de novo synthesis (serine palmitoyltransferase-dependent) and acid sphingomyelinase (ASMase) activation; ceramide mediates ER stress induction (blocking ceramide synthesis blocks BiP/GRP78, GADD153, phospho-eIF2α induction). Ceramide activates protein phosphatase 2A (PP2A), leading to dephosphorylation of anti-apoptotic BCL-2.\",\n      \"method\": \"Lipidomic analysis of ceramide species (C16, C24, C24:1), SPT inhibitor myriocin (ISP1), fumonisin B1, ASMase siRNA knockdown, PP2A activity assay, Western blotting for ER stress markers\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct ceramide quantification by lipidomics, enzyme inhibitors, siRNA knockdown, and PP2A activity assay converge on mechanistic conclusion\",\n      \"pmids\": [\"19937735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In prostate cancer cells, Ad.mda-7 induces early autophagy that switches to apoptosis; MDA-7/IL-24 protein physically interacts with Beclin-1 (potentially inhibiting its autophagy-promoting function), and calpain-mediated cleavage of ATG5 contributes to the autophagy-to-apoptosis switch.\",\n      \"method\": \"Co-immunoprecipitation (MDA-7/IL-24 with Beclin-1), autophagy and apoptosis markers, calpain inhibitor studies\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP identifies physical interaction with Beclin-1; calpain inhibitor experiments support ATG5 cleavage mechanism; single lab\",\n      \"pmids\": [\"21610321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MDA-7/IL-24 differentially regulates clusterin (CLU) in prostate cancer cells: Ad.mda-7 decreases soluble CLU (sCLU) and increases nuclear CLU (nCLU), promoting apoptosis and G2/M arrest. MDA-7/IL-24 was identified as a CLU-interacting protein by co-immunoprecipitation in DU-145 cells, and the initial sCLU-MDA-7/IL-24 interaction produces a transient cytoprotective effect.\",\n      \"method\": \"Co-immunoprecipitation (MDA-7/IL-24 with CLU), stable CLU overexpressing clones, Western blotting, cell viability and apoptosis assays, xenograft mouse models\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP identifies physical interaction; stable cell lines and xenograft validate functional consequences; single lab\",\n      \"pmids\": [\"21732348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MDA-7/IL-24 induces expression of SARI (suppressor of AP-1, induced by IFN) in diverse cancer cells but not normal cells, and SARI expression is required for mda-7/IL-24-mediated cell death (SARI antisense blocked mda-7/IL-24 antitumor effects). Binding of secreted MDA-7/IL-24 to its cognate receptors (IL-20R1/IL-20R2 or IL-22R/IL-20R2) induces p38 MAPK phosphorylation, leading to GADD gene transcription and apoptosis; p38 MAPK inhibition prevented SARI induction by Ad.mda-7.\",\n      \"method\": \"SARI antisense knockdown, p38 MAPK inhibitor, receptor-binding studies with recombinant His-MDA-7, Western blotting, cell death assays; ERK1/2 inhibitor reversal in pancreatic cancer cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antisense knockdown demonstrates SARI requirement; p38 MAPK inhibitor and His-MDA-7 receptor engagement experiments define pathway; single lab\",\n      \"pmids\": [\"24282278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-24 inhibits lung cancer cell migration and invasion by post-transcriptionally downregulating CXCR4 mRNA (decreasing mRNA half-life by >40%), thereby disrupting the SDF-1/CXCR4 signaling axis and reducing pAKT, pmTOR, pPRAS40, and HIF-1α. Combined IL-24 with CXCR4 inhibitors (AMD3100, SJA5) or CXCR4 siRNA showed enhanced inhibition of tumor cell migration.\",\n      \"method\": \"Doxycycline-inducible stable IL-24 expression, qRT-PCR mRNA half-life assay, Western blotting for CXCR4 and downstream signaling, flow cytometry, cell migration/invasion assays, luciferase reporter assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible expression system, mRNA stability assay, multiple functional readouts, single lab\",\n      \"pmids\": [\"25775124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MDA-7/IL-24 downregulates miR-221 and upregulates p27 and PUMA in cancer cells; this effect is ROS-dependent and leads to cell death. MDA-7/IL-24 regulates autophagy through a miR-221/Beclin-1 feedback loop (Beclin-1 identified as a new transcriptional target of miR-221). Overexpression of miR-221 rescues cancer cells from mda-7/IL-24-mediated death.\",\n      \"method\": \"miRNA profiling, overexpression of miR-221, recombinant His-MDA-7 protein treatment, ROS measurement, Western blotting (p27, PUMA, Beclin-1), xenograft model with miR-221-overexpressing cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple approaches (miRNA profiling, gain-of-function rescue, in vivo xenograft), single lab\",\n      \"pmids\": [\"27940575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"mda-7/IL-24 induces caspase-3/9-independent apoptosis in neuroblastoma cells through a pathway involving ATM phosphorylation, γ-H2AX induction, and nuclear translocation of apoptosis-inducing factor (AIF). Inhibition of AIF rescued cells from Ad.5/3-CTV-induced death, while pan-caspase inhibition failed. ATM small-molecule inhibitors blocked γ-H2AX, AIF translocation, and PARP cleavage.\",\n      \"method\": \"AIF siRNA knockdown, ATM inhibitors, pan-caspase inhibitor (z-VAD), Western blotting (γ-H2AX, phospho-ATM, AIF), nuclear fractionation, in vivo xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown plus pharmacological ATM inhibitors with convergent results, in vivo validation, single lab\",\n      \"pmids\": [\"27197168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-24 promotes apoptosis in breast cancer cells through cAMP-dependent PKA activation, which is required for IL-24-induced cell death; PKA stimulates p38 MAPK phosphorylation, upregulates Fas/FasL pathway components and death receptor 4, and induces phosphorylation and nuclear import of TP53.\",\n      \"method\": \"PKA inhibition/activation pharmacological studies, Western blotting (phospho-p38, phospho-TP53, FasL, DR4), cell viability assays, nuclear fractionation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with multiple readouts; single lab; methods partly inferred from abstract\",\n      \"pmids\": [\"30424508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MDA-7/IL-24 downregulates DICER (a key miRNA processing enzyme) in multiple cancer cells but not normal cells, through IL-20/IL-22 receptors; this is ROS-dependent and mediated through melanogenesis-associated transcription factor (MITF). DICER overexpression partially rescues cancer cells from mda-7/IL-24-mediated cell death and impedes mda-7/IL-24 inhibition of tumor growth in vivo.\",\n      \"method\": \"Gain- and loss-of-function studies (DICER overexpression/knockdown), recombinant His-MDA-7 protein, Western blotting (DICER, DROSHA, PASHA, Argonaute), receptor neutralization, ROS measurement, xenograft tumor model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (receptor neutralization, DICER gain/loss-of-function, in vivo validation, MITF pathway), replicated with both adenoviral and recombinant protein delivery\",\n      \"pmids\": [\"30842276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The mda-7 gene promoter contains functional binding sites for AP-1 (c-Jun) and C/EBP transcription factors; ectopic expression of AP-1/c-Jun or C/EBP enhances mda-7 promoter activity in melanoma cells while a dominant-negative c-Jun (TAM67) does not. Electrophoretic mobility shift assays (EMSA) confirmed binding of nuclear proteins from terminally differentiated melanoma cells to AP-1 and C/EBP consensus sites in the mda-7 promoter.\",\n      \"method\": \"Luciferase reporter assay (mda-7 promoter-luciferase), EMSA with nuclear extracts, Western blotting (cJun, C/EBP-beta), dominant-negative c-Jun overexpression\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay, EMSA, and dominant-negative mutant converge on mechanism; single lab\",\n      \"pmids\": [\"10942517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"FISP (murine IL-24 ortholog) is selectively expressed and secreted by Th2 cells; its expression during Th2 differentiation requires two signals: TCR signaling involving protein kinase C activation, and STAT6-dependent IL-4 receptor signaling.\",\n      \"method\": \"Differential gene expression during Th1/Th2 differentiation, PKC activation/inhibition, STAT6-deficient cells, secretion assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (STAT6-deficient) and pharmacological dissection of signaling requirements; single lab\",\n      \"pmids\": [\"11342597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-17A triggers a Th17 cell-intrinsic autocrine negative feedback loop: IL-17A binds its receptor on Th17 cells, activates NF-κB, which induces IL-24 expression; IL-24 in turn represses the Th17 cytokine program (GM-CSF, IL-17F). In vivo, IL-24 treatment ameliorated Th17-induced EAU, while IL-24 silencing in Th17 cells enhanced disease.\",\n      \"method\": \"IL-17A loss-of-function in Th17 cells, mechanistic in vitro NF-κB activation studies, IL-24 silencing in Th17 cells, IL-24 treatment of EAU mouse model, cytokine measurements\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection with genetic knockdown, pharmacological NF-κB studies, in vivo disease model, replicated in human Th17 cells; high-quality journal\",\n      \"pmids\": [\"32673565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-24 protein accumulates in the cytosol under conditions of proteasome dysfunction (when ER-associated degradation is blocked), and cytoplasmic IL-24 activates PKR (protein kinase R), which serves as an innate immune sensor for proteotoxic stress. PKR activation by cytoplasmic IL-24 drives NF-κB and type I IFN signaling; PKR also phosphorylates eIF2α to limit new protein translation. Blocking IL-24 egress into the cytosol (by inhibiting ERAD) suppressed PKR activation and downstream inflammatory signaling.\",\n      \"method\": \"PKR genetic deletion in vitro and in vivo (PKR-deficient mice), proteasome inhibitor-induced inflammatory models, ERAD inhibition to block cytoplasmic IL-24 accumulation, eIF2α phosphorylation assays, patient cells from PRAAS\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deletion of PKR in vitro and in vivo, ERAD inhibition to block IL-24 cytosol accumulation, multiple cell types including patient samples, mechanistically rigorous\",\n      \"pmids\": [\"35148201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Th17 cells, IL-24 is recruited to the inner mitochondrial membrane where it interacts with NADH dehydrogenase (ubiquinone) 1 α subcomplex subunit 13 (GRIM19/NDUFA13), a complex I respiratory chain component. Together, IL-24 and GRIM19 promote accumulation of STAT3 in the mitochondrial compartment, limiting STAT3 nuclear deflections and promoting IL-10 production to restrain Th17 pathogenicity. This function is independent of IL-24 cell surface receptor signaling.\",\n      \"method\": \"Mitochondrial fractionation, co-immunoprecipitation (IL-24 with GRIM19), STAT3 mitochondrial localization assays, receptor-independent signaling experiments, EAU model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP demonstrating physical interaction, mitochondrial fractionation showing localization, receptor-independence established, functional consequence (STAT3 compartmentalization, IL-10) demonstrated\",\n      \"pmids\": [\"35819408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A novel splice variant of mda-7/IL-24 (mda-7s), encoding a 63-residue 12 kDa protein lacking exons 3 and 5, co-precipitates full-length MDA-7 and reduces secretion of co-transfected MDA-7 protein.\",\n      \"method\": \"Co-immunoprecipitation (mda-7s with full-length MDA-7), secretion assays, RT-PCR expression analysis\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP experiment; functional significance of interaction not elaborated; single lab\",\n      \"pmids\": [\"15304100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-24 deficiency protects mice from bleomycin-induced pulmonary fibrosis; mechanistically, IL-24 synergizes with IL-4 to promote macrophage M2 polarization by suppressing IL-4-induced SOCS1 and SOCS3 expression, thereby enhancing STAT6/PPARγ signaling.\",\n      \"method\": \"IL-24 knockout mice, bleomycin fibrosis model, macrophage M2 polarization assays, Western blotting (SOCS1, SOCS3, STAT6, PPARγ), cytokine quantification (TGF-β1)\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout model, mechanistic pathway dissection (SOCS1/3-STAT6/PPARγ), in vivo and in vitro convergent evidence, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33144678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In CLL B-cells, MDA-7/IL-24 activates p38 MAPK, and this activation is required for CLL cell survival; siRNA knockdown of mda-7/IL-24 specifically inhibited p38 MAPK phosphorylation and increased spontaneous apoptosis three-fold. Recombinant IL-24 could re-induce p38 MAPK phosphorylation.\",\n      \"method\": \"siRNA knockdown of mda-7/IL-24, p38 MAPK pharmacological inhibitor (SB203580), recombinant IL-24 protein treatment, Western blotting, apoptosis assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown plus pharmacological inhibitor plus recombinant protein rescue; single lab\",\n      \"pmids\": [\"16408101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Recombinant MDA-7/IL-24 protein inhibits prostate cancer bone metastasis by both selectively killing prostate cancer cells and inhibiting osteoclast differentiation. Gain- and loss-of-function studies show that the Akt and Mcl-1 prosurvival pathways are critically required for anti-bone metastatic activity of MDA-7/IL-24.\",\n      \"method\": \"Bone metastasis experimental model, gain/loss-of-function genetic approaches (Akt, Mcl-1), Mcl-1 small-molecule inhibitor, in vivo femur metastasis quantification, Western blotting\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic gain/loss-of-function plus in vivo model; single lab\",\n      \"pmids\": [\"29934341\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-24 (MDA-7) is a secreted IL-10-family cytokine that signals through two heterodimeric receptors (IL-22R1/IL-20R2 and IL-20R1/IL-20R2) to activate STAT transcription factors; at supra-physiological levels it induces cancer-selective apoptosis and toxic autophagy by triggering endoplasmic reticulum stress (via PERK/eIF2α phosphorylation), ceramide generation (through de novo synthesis and acid sphingomyelinase), and activation of p38 MAPK and JNK signaling, while in immune contexts it operates through an autocrine loop in Th17 cells—recruiting to the inner mitochondrial membrane to interact with GRIM19 and promote mitochondrial STAT3 accumulation—and also acts as a cytoplasmic danger-associated molecular pattern that activates PKR under proteotoxic stress conditions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-24 (MDA-7) is a secreted IL-10-family cytokine that signals through two heterodimeric type II receptor complexes (IL-22R1/IL-20R2 and IL-20R1/IL-20R2) to activate STAT transcription factors on keratinocytes and other targets [#0]. Its best-characterized role is as a cancer-selective cytotoxic effector: at high intracellular levels IL-24 localizes to the endoplasmic reticulum and triggers a tumor-restricted ER stress program (BiP/GRP78, GRP94, GADD153, phospho-eIF2\\u03b1) through physical interaction with the chaperone BiP/GRP78, killing cancer but not normal cells via JAK/STAT-independent, p38 MAPK-dependent signaling [#11, #12]. This lethality proceeds through PERK-dependent ER stress that activates JNK and BAX-driven mitochondrial dysfunction and a coupled toxic autophagy program requiring ATG5 and Beclin-1 [#13], with de novo and acid-sphingomyelinase-driven ceramide generation upstream\\u2014ceramide clusters CD95/Fas, activates PP2A to dephosphorylate BCL-2, and feeds the ER stress response [#14, #15]. Downstream death is executed through transcriptional induction of the Fas/FasL axis via c-Jun/ATF-2 [#8] and the IFN-inducible mediator SARI [#18], while IL-24 also represses pro-survival and metastatic signaling (\\u03b2-catenin, PI3K/AKT, FAK, MMPs, CXCR4) and suppresses NHEJ repair to radiosensitize tumors [#3, #5, #19]. Distinct from these cytotoxic functions, IL-24 acts as an intrinsic immune regulator: in Th17 cells it is induced by IL-17A/NF-\\u03baB as an autocrine brake on the pathogenic cytokine program [#26] and, independent of surface receptor signaling, is recruited to the inner mitochondrial membrane where it binds GRIM19/NDUFA13 to promote mitochondrial STAT3 retention and IL-10 production [#28]. Under proteotoxic stress, cytosolic IL-24 accumulating after blocked ER-associated degradation activates PKR, driving eIF2\\u03b1 phosphorylation, NF-\\u03baB, and type I IFN signaling as an innate sensor of proteostasis collapse [#27].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established how the mda-7/IL-24 gene itself is transcriptionally controlled, identifying the regulatory inputs that drive its expression in differentiating melanoma cells.\",\n      \"evidence\": \"Promoter-luciferase, EMSA, and dominant-negative c-Jun in melanoma cells\",\n      \"pmids\": [\"10942517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address protein function downstream of expression\", \"Restricted to melanoma context\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined IL-24 as a bona fide cytokine ligand by showing it binds two heterodimeric type II receptor complexes and activates STATs, placing it in canonical cytokine signaling.\",\n      \"evidence\": \"Ligand-receptor binding assays and STAT activation on keratinocytes and transfected cells\",\n      \"pmids\": [\"11706020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not explain cancer-selective cytotoxicity\", \"Physiological target tissues incompletely mapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed the murine ortholog (FISP) is a Th2-restricted secreted product requiring TCR/PKC and STAT6 signals, giving IL-24 an early immune-cell identity beyond epithelial signaling.\",\n      \"evidence\": \"Th1/Th2 differentiation profiling, PKC modulation, STAT6-deficient cells\",\n      \"pmids\": [\"11342597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Th2 secretion not defined\", \"Ortholog data may not fully translate to human\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Decoupled IL-24's cytokine receptor/STAT signaling from its tumor-killing activity, demonstrating apoptosis proceeds through JAK/STAT-independent, p38 MAPK-dependent routes.\",\n      \"evidence\": \"Kinase inhibitors and JAK/STAT-deficient cancer lines with apoptosis readouts\",\n      \"pmids\": [\"12811827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the receptor-independent intracellular trigger\", \"p38 only partially required\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked IL-24 to suppression of oncogenic signaling, showing it down-regulates \\u03b2-catenin/TCF and PI3K/AKT outputs in a tumor-selective manner.\",\n      \"evidence\": \"Microarray, Western blot, TCF/LEF reporter, PI3K inhibition in breast/lung cells\",\n      \"pmids\": [\"12907143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking IL-24 to pathway suppression unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Began assembling the death machinery downstream of IL-24, identifying ROS- and JNK-dependent BAX activation and the intrinsic caspase-9 pathway, and showing migration/invasion suppression via PI3K/FAK/MMP down-regulation.\",\n      \"evidence\": \"ROS scavengers, JNK inhibitors, caspase inhibitors, migration/invasion and in vivo metastasis assays\",\n      \"pmids\": [\"15197348\", \"15093181\", \"15564140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream ER signal not yet defined\", \"Parallel ROS-dependent and -independent arms not fully resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected IL-24 to radiosensitization by showing it suppresses NHEJ DNA repair components and impairs double-strand break rejoining.\",\n      \"evidence\": \"Western blot, pulsed-field gel electrophoresis, host-cell reactivation in NSCLC\",\n      \"pmids\": [\"15273727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Ku70/XRCC4/ligase IV down-regulation unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified the Fas/FasL death-receptor axis as a transcriptional effector of IL-24 killing, driven by c-Jun/ATF-2 and NF-\\u03baB.\",\n      \"evidence\": \"Fas siRNA, FasL neutralizing antibody, promoter-reporter, apoptosis assays in ovarian cancer\",\n      \"pmids\": [\"15833826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link to upstream ER/ceramide signaling not yet drawn\", \"Cell-type generality untested here\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the secreted, bystander-acting nature of IL-24 toxicity, showing conditioned medium sensitizes endothelium and kills non-transduced tumor cells through IL-20 receptor engagement.\",\n      \"evidence\": \"Conditioned medium clonogenic assays, neutralizing anti-MDA-7/anti-IL-20R antibodies, xenograft histology\",\n      \"pmids\": [\"15194048\", \"15851011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of receptor-dependent bystander killing with receptor-independent intracellular killing unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed a context-dependent pro-survival role: in CLL B-cells endogenous IL-24 sustains p38 MAPK signaling required for survival, contrasting with its cytotoxic action in solid tumors.\",\n      \"evidence\": \"IL-24 siRNA knockdown, SB203580, recombinant IL-24 rescue, apoptosis assays\",\n      \"pmids\": [\"16408101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis for opposite p38 outcomes across cell types unexplained\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Separated IL-24's intracellular cytotoxic function from secretion and glycosylation, showing a nonsecreted, nonglycosylated mutant retains ER localization, BiP/GRP78 binding, and tumor-selective ER-stress killing.\",\n      \"evidence\": \"Site-directed mutagenesis, co-IP with BiP/GRP78, ER stress marker Western blots, apoptosis assays\",\n      \"pmids\": [\"17178884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not explain why ER stress is tumor-selective\", \"BiP/GRP78 interaction's mechanistic consequence not fully defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Built the core ER-stress death pathway, placing PERK upstream of JNK/BAX and a coupled toxic autophagy program, and uncovering an autocrine loop stabilizing IL-24 mRNA to sustain the response.\",\n      \"evidence\": \"PERK-/- cells, ATG5/Beclin-1 siRNA, mRNA stability and protein-synthesis inhibition, ROS measurement in glioma and other cancers\",\n      \"pmids\": [\"18281515\", \"18599461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger of initial ER stress not yet identified\", \"Autophagy-apoptosis switch mechanism incomplete\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Inserted ceramide and CD95 clustering upstream of ER stress, ordering CD95 above PERK in the killing cascade.\",\n      \"evidence\": \"siRNA of CD95, ceramide synthase-6, ASMase; dominant-negative PERK; caspase-8 inhibitor in renal carcinoma\",\n      \"pmids\": [\"19417161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IL-24 initiates ceramide generation unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the lipid trigger of IL-24 lethality, showing tumor-selective ceramide accumulation via de novo synthesis and ASMase drives ER stress and PP2A-mediated BCL-2 dephosphorylation.\",\n      \"evidence\": \"Lipidomics, SPT/ceramide synthase inhibitors, ASMase siRNA, PP2A activity assay\",\n      \"pmids\": [\"19937735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sensor connecting IL-24 to ceramide enzymes unidentified\", \"Tumor-selectivity basis unexplained\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified Beclin-1 as a direct IL-24 binding partner and a calpain/ATG5 mechanism governing the autophagy-to-apoptosis switch.\",\n      \"evidence\": \"Co-IP of IL-24 with Beclin-1, calpain inhibitors, autophagy/apoptosis markers in prostate cancer\",\n      \"pmids\": [\"21610321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Beclin-1 binding inferred, not directly demonstrated\", \"Single Co-IP\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Expanded IL-24's interactome to clusterin, distinguishing a transient sCLU-mediated cytoprotection from nCLU-driven apoptosis.\",\n      \"evidence\": \"Co-IP of IL-24 with CLU, stable CLU clones, xenografts in prostate cancer\",\n      \"pmids\": [\"21732348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect interaction not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified SARI as a required transcriptional effector downstream of receptor-engaged, p38-driven IL-24 signaling, linking the cytokine arm to cancer-selective death.\",\n      \"evidence\": \"SARI antisense, p38 inhibitor, His-MDA-7 receptor binding in diverse cancers\",\n      \"pmids\": [\"24282278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How SARI executes death not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended IL-24's anti-metastatic action by showing post-transcriptional CXCR4 mRNA destabilization disrupts the SDF-1/CXCR4 axis and downstream AKT/mTOR/HIF-1\\u03b1 signaling.\",\n      \"evidence\": \"Inducible IL-24 expression, mRNA half-life qRT-PCR, migration/invasion assays in lung cancer\",\n      \"pmids\": [\"25775124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of mRNA destabilization unidentified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked IL-24 to miRNA control, showing ROS-dependent miR-221 down-regulation derepresses p27/PUMA and a miR-221/Beclin-1 feedback loop regulates autophagy.\",\n      \"evidence\": \"miRNA profiling, miR-221 overexpression rescue, His-MDA-7, xenografts\",\n      \"pmids\": [\"27940575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Connection to core ER-stress pathway unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered a caspase-independent death route via ATM activation, \\u03b3-H2AX, and nuclear AIF translocation in neuroblastoma.\",\n      \"evidence\": \"AIF siRNA, ATM inhibitors, pan-caspase inhibitor, nuclear fractionation, xenograft\",\n      \"pmids\": [\"27197168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trigger of ATM activation by IL-24 unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Added cAMP/PKA as an upstream activator coupling IL-24 to p38, Fas/FasL/DR4, and TP53 nuclear import in breast cancer, and defined Akt/Mcl-1 dependence of anti-bone-metastatic activity.\",\n      \"evidence\": \"PKA pharmacology, Western blots, nuclear fractionation; gain/loss-of-function of Akt/Mcl-1 in bone metastasis model\",\n      \"pmids\": [\"30424508\", \"29934341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How IL-24 raises cAMP/PKA not defined\", \"Context-dependent pro-survival vs pro-death roles unreconciled\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected IL-24 to global miRNA biogenesis, showing receptor- and ROS/MITF-dependent down-regulation of DICER as a tumor-selective death mechanism.\",\n      \"evidence\": \"Receptor neutralization, DICER gain/loss-of-function, His-MDA-7, xenografts\",\n      \"pmids\": [\"30842276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between DICER loss and apoptosis execution incomplete\", \"MITF regulation mechanism partial\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a physiological immunoregulatory function: IL-17A/NF-\\u03baB induces IL-24 in Th17 cells as an autocrine brake that represses the pathogenic Th17 cytokine program.\",\n      \"evidence\": \"IL-17A loss-of-function, NF-\\u03baB studies, IL-24 silencing, EAU model in mouse and human Th17 cells\",\n      \"pmids\": [\"32673565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which IL-24 represses Th17 cytokines not fully defined here\", \"Receptor dependence of this loop not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a pro-fibrotic role through macrophage polarization, where IL-24 synergizes with IL-4 by suppressing SOCS1/3 to enhance STAT6/PPAR\\u03b3-driven M2 polarization.\",\n      \"evidence\": \"IL-24 knockout mice, bleomycin fibrosis model, M2 polarization assays, SOCS/STAT6/PPAR\\u03b3 Western blots\",\n      \"pmids\": [\"33144678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating macrophage effect not specified\", \"Relationship to cytotoxic functions unaddressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established receptor-independent intracellular roles for IL-24: as a cytosolic DAMP activating PKR under proteotoxic stress, and as an inner-mitochondrial-membrane GRIM19 partner directing mitochondrial STAT3 and IL-10 in Th17 cells.\",\n      \"evidence\": \"PKR-deficient mice, ERAD inhibition, PRAAS patient cells; mitochondrial fractionation and co-IP with GRIM19/NDUFA13 in Th17 cells\",\n      \"pmids\": [\"35148201\", \"35819408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of IL-24 cytosol egress incompletely defined\", \"How a single protein partitions between secreted, ER, mitochondrial, and cytosolic roles unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how IL-24's tumor-selective intracellular ceramide/ER-stress death program, its receptor-dependent STAT cytokine signaling, and its receptor-independent mitochondrial/cytosolic immune functions are mechanistically coordinated, and what determines its opposite pro- vs anti-survival outcomes across cell types.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking secreted, ER, mitochondrial, and cytosolic IL-24 pools\", \"Basis of cancer-cell selectivity for ceramide/ER stress unidentified\", \"Determinants of pro-survival (CLL) vs pro-death (solid tumor) responses unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 4, 18, 23]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [11, 14, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11, 16, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [11, 12, 13]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 4, 10]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [28]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8, 13, 14, 21]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [12, 13, 15, 27]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [26, 27, 28, 30]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 18]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13, 16, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HSPA5\", \"BECN1\", \"CLU\", \"NDUFA13\", \"EIF2AK2\", \"STAT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}