{"gene":"CERS6","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2005,"finding":"CERS6 (Lass6) encodes a ceramide synthase that preferentially produces short-chain ceramides (C14:0 and C16:0) when overexpressed in cultured cells, with a distinct substrate preference for saturated/unsaturated fatty acyl-CoA compared to Lass5. The N-terminus of CERS6 faces the luminal side of the ER membrane (demonstrated by N-glycosylation of the N-terminal Asn residue), while the C-terminus faces the cytosolic side (demonstrated by proteinase K digestion assay), establishing the topology of the conserved Lag1 motif.","method":"Overexpression in cultured cells with ceramide species profiling; N-glycosylation analysis; proteinase K digestion assay; Northern blotting for tissue expression","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods (ceramide profiling, glycosylation, protease protection) in a single rigorous study establishing substrate specificity and membrane topology","pmids":["15823095"],"is_preprint":false},{"year":2005,"finding":"LASS6 (CERS6) protein contains a homeodomain and LAG1 domain, maps to human chromosome 2q24.3, and is conserved in vertebrates (mouse and zebrafish orthologs identified). The gene spans ~318 kb and is broadly expressed across tissues.","method":"Bioinformatic/genomic database screening and phylogenetic analysis; in silico expression analysis","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 4 / Weak — purely computational/bioinformatic characterization with no direct functional experiment","pmids":["16211262"],"is_preprint":false},{"year":2014,"finding":"CerS6 is the ceramide synthase responsible for C16:0 ceramide production in adipose tissue and liver; whole-body and tissue-specific (BAT- and liver-specific) CerS6 knockout mice show reduced C16:0 ceramides, increased energy expenditure, and protection from high-fat-diet-induced obesity and glucose intolerance, placing CerS6-derived C16:0 ceramide as a mediator of metabolic dysfunction in obesity.","method":"Conditional knockout mouse models (whole-body, BAT-specific, liver-specific CerS6 deletion); ceramide profiling by mass spectrometry; metabolic phenotyping (glucose tolerance tests, energy expenditure measurements)","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple tissue-specific KO mouse models with ceramide profiling and metabolic phenotyping, replicated across tissue contexts in a single rigorous study","pmids":["25295788"],"is_preprint":false},{"year":2016,"finding":"CerS6 is a direct transcriptional target of p53: the CerS6 promoter is activated by p53 in luciferase assays (transcriptionally inactive R175H mutant fails to activate), purified p53 binds within the CerS6 promoter (91 bp upstream to 60 bp downstream of TSS) as shown by in vitro immunoprecipitation and gel shift assays, with a single non-canonical p53 response element upstream of the TSS identified as the key binding motif. Treatment with Nutlin-3 or low-dose actinomycin D (non-genotoxic p53 activators) elevates CerS6 mRNA and protein.","method":"Luciferase reporter assays with wild-type vs. R175H p53 mutant; in vitro immunoprecipitation; electrophoretic mobility shift assay (EMSA/gel shift); pharmacological p53 activation (Nutlin-3, actinomycin D)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (luciferase, in vitro IP, gel shift, mutagenesis of p53, pharmacological validation) in a single study establishing direct p53-CerS6 promoter interaction","pmids":["27302066"],"is_preprint":false},{"year":2016,"finding":"Silencing of CerS6 in melanoma cell lines increases invasion and glycolysis by upregulating GLUT1 expression, which in turn downregulates WNT5A. Silencing GLUT1 in CerS6-silenced cells restores WNT5A expression and reduces invasion/proliferation, placing CerS6 upstream of a GLUT1/WNT5A axis regulating melanoma malignancy.","method":"siRNA-mediated CerS6 knockdown; gene microarray; qPCR and western blot validation; invasion and proliferation assays; GLUT1 silencing rescue experiment","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — epistasis established by rescue experiment with GLUT1 silencing; multiple cell lines tested but single lab","pmids":["26934938"],"is_preprint":false},{"year":2018,"finding":"CerS6 overexpression in cisplatin-resistant oral squamous cell carcinoma (OSCC) cells restores cisplatin sensitivity by enhancing mitochondrial fission, promoting apoptosis, and attenuating cisplatin-induced autophagy; this is associated with altered calpain expression. CerS6 knockdown has the opposite effect.","method":"Lentiviral CerS6 overexpression in resistant cells; mitochondrial morphology assessment; apoptosis assays; autophagy marker analysis; xenograft tumor model","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — gain-of-function and loss-of-function with defined cellular phenotypes (mitochondrial fission, apoptosis, autophagy) plus in vivo validation; single lab","pmids":["30054909"],"is_preprint":false},{"year":2019,"finding":"Antisense oligonucleotide (ASO)-mediated knockdown of CerS6 predominantly in the liver (~90% reduction in CerS6 mRNA) reduces C16:0 ceramide levels by ~50% in liver and plasma, decreases body weight gain, reduces fat mass, lowers blood glucose (HbA1c), and improves oral glucose tolerance and insulin sensitivity in ob/ob and HFD-induced obese mouse models, confirming CerS6 as a therapeutically actionable target for hepatic C16:0 ceramide production.","method":"Antisense oligonucleotide (ASO) pharmacological knockdown in vivo; ceramide profiling; glucose and insulin tolerance tests; body composition analysis in two obese mouse models","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological knockdown in two independent disease models with ceramide profiling and metabolic phenotyping, corroborating genetic KO data from PMID 25295788","pmids":["30655217"],"is_preprint":false},{"year":2020,"finding":"CERS6 is required for cell migration and invasion in non-small cell lung cancer (NSCLC): CERS6 knockdown alters the ceramide profile, suppresses RAC1-positive lamellipodia/ruffling formation, reduces cell migration in vitro, and attenuates lung metastasis in mice; forced CERS6 expression produces the opposite phenotype. CERS6 overexpression in NSCLC is driven at least in part by reduced miR-101 expression.","method":"CERS6 knockdown and overexpression in NSCLC cell lines; ceramide profiling; RAC1 localization/lamellipodia assays; in vivo lung metastasis mouse model; luciferase analysis for miR-101 regulation","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with in vitro and in vivo validation, ceramide profiling, and mechanistic pathway (RAC1/lamellipodia); single lab","pmids":["32902157"],"is_preprint":false},{"year":2021,"finding":"CEBPγ transcription factor directly binds the Y-box cis-acting element in the CERS6 promoter to induce CERS6 expression, promoting ceramide-dependent lamellipodia formation and cell migration in NSCLC. YBX1 independently regulates lamellipodia and migration but without specific binding to the Y-box for CERS6 induction.","method":"Luciferase analysis of CERS6 promoter; siRNA knockdown of CEBPγ and YBX1; correlation analysis in 149 NSCLC patient database records; lamellipodia and migration assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — promoter luciferase with knockdown and phenotypic validation; single lab, no ChIP confirmation of direct binding","pmids":["33934437"],"is_preprint":false},{"year":2021,"finding":"AKT1 phosphorylates FOXP3 at S418, which decreases FOXP3 binding to the CERS6 promoter and thereby induces CerS6 expression. CerS6-derived C16-ceramide produced downstream promotes accumulation of mutant p53 in pancreatic ductal adenocarcinoma. This AKT1/FOXP3 axis drives CERS6 transcription and pancreatic tumorigenesis.","method":"Co-immunoprecipitation (AKT1-FOXP3 interaction); phosphorylation assays (S418 site); chromatin immunoprecipitation (FOXP3 binding to CERS6 promoter); CerS6 overexpression/knockdown; ceramide profiling; colony formation, invasion, and tumor formation assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and phosphorylation assays establish the regulatory axis; single lab with multiple methods","pmids":["34343636"],"is_preprint":false},{"year":2023,"finding":"CERS6 and LASP1 form a direct protein complex (with the LASP1 LIM domain likely required for interaction) that co-localizes on lamellipodia in lung cancer cell lines. Both CERS6 and LASP1 independently co-immunoprecipitate with actin, but these interactions are markedly reduced when the LASP1-CERS6 complex is abolished. Silencing either CERS6 or LASP1 suppresses cell migration and lamellipodia formation; ectopic addition of C16 ceramide partially rescues these phenotypes.","method":"Co-immunoprecipitation; liquid chromatography-tandem mass spectrometry (LC-MS/MS) for binding partner identification; co-localization microscopy; siRNA knockdown of CERS6 and/or LASP1; cell migration and lamellipodia formation assays; C16 ceramide rescue experiment","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with MS identification of binding partner, co-localization, reciprocal knockdowns, and ceramide rescue; single lab","pmids":["37345118"],"is_preprint":false},{"year":2023,"finding":"CerS6 deficiency in hypothalamic neurons (conditional KO) attenuates HFD-induced weight gain and improves glucose metabolism. Neuron-specific CerS6 deletion in POMC-expressing cells prevents diet-induced mitochondrial morphology alterations and improves cellular leptin sensitivity, while CerS6 deletion in SF-1-expressing neurons alters feeding behavior and alleviates adverse metabolic effects. CerS6-derived ceramides promote ER/mitochondrial stress in hypothalamic lipotoxicity.","method":"Conditional neuronal CerS6 knockout mice (POMC-Cre and SF-1-Cre drivers); mitochondrial morphology analysis; leptin sensitivity assays; metabolic phenotyping (glucose tolerance, insulin sensitivity, body weight, food intake); palmitate treatment of cultured hypothalamic neurons in vitro","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with multiple mechanistic readouts (mitochondrial morphology, leptin signaling, ER stress) across two distinct neuron populations; rigorous in vivo study","pmids":["38016943"],"is_preprint":false},{"year":2023,"finding":"CERS6-derived C16:0 ceramide (and C14:0 ceramide) inhibit PINK1-mediated mitophagy in renal tubular epithelial cells, likely by binding directly to the PINK1 protein (supported by automated docking analysis). CerS6 deficiency in db/db diabetic mice restores PINK1/Parkin-mediated mitophagy, reduces damaged mitochondria, and attenuates interstitial fibrosis. Inhibiting PINK1 in CERS6-knockdown HK-2 cells abolishes the protective effect.","method":"CerS6 knockout in db/db mice; ceramide profiling (LC-MS/MS); mitophagy assays (PINK1/Parkin pathway markers); CERS6 knockdown in HK-2 cells with PINK1 inhibition rescue; automated molecular docking of ceramides to PINK1","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vivo KO with mitophagy readouts and epistasis via PINK1 inhibition rescue; direct ceramide-PINK1 binding supported only by docking (not biochemically validated)","pmids":["37458434"],"is_preprint":false},{"year":2023,"finding":"High glucose promotes CerS6 synthesis through the TLR4/IKKβ signaling pathway in human liver (LO2) cells. CerS6-derived ceramide promotes mitochondrial oxidative stress (mtROS), and CerS6 knockout attenuates mitochondrial oxidative stress, inhibits ferroptosis, and ameliorates markers of liver injury and fibrosis under high-glucose conditions.","method":"Pharmacological TLR4/IKKβ pathway manipulation; CerS6 knockdown and overexpression in LO2 cells; mitochondrial ROS measurement; ferroptosis marker analysis; Mito-TEMPO antioxidant intervention","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pathway epistasis via pharmacological inhibition and rescue, with KO/OE and mechanistic readouts; single lab, in vitro","pmids":["37230220"],"is_preprint":false},{"year":2024,"finding":"FTO (m6A demethylase) deficiency increases m6A modification on CerS6 mRNA, decreasing its stability and reducing CerS6 expression in intestinal epithelial cells. Reduced CerS6 leads to S1P accumulation, which triggers proinflammatory macrophage activation (secreting SAA1/3) and ultimately induces Th17 cell differentiation, aggravating ulcerative colitis.","method":"Conditional FTO knockout mice (Villin-Cre); RNA and methylated RNA immunoprecipitation sequencing (MeRIP-seq); ceramide/S1P profiling by LC-MS; macrophage conditioned medium treatment; real-time PCR and 16S rRNA sequencing","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO combined with MeRIP-seq establishing the m6A-CerS6 mRNA stability mechanism, ceramide/S1P profiling, and immune cell functional readouts; multiple orthogonal methods","pmids":["37734910"],"is_preprint":false},{"year":2024,"finding":"CerS6-derived ceramide (d18:1/16:0) binds to the mitochondrial channel protein VDAC1 at Glu59, initiating mitochondrial DNA (mtDNA) leakage, activating the cGAS-STING signaling pathway, and promoting inflammatory responses in kidney podocytes in diabetic kidney disease. Podocyte-specific CerS6 knockout ameliorates glomerular injury and inflammation, while podocyte-specific CerS6 overexpression induces proteinuria.","method":"Podocyte-specific CerS6 knockout and overexpression in diabetic mice; ceramide-VDAC1 binding analysis (including identification of Glu59 residue); mtDNA leakage assays; cGAS-STING pathway activation measurement; histology and proteinuria assessment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific gain and loss of function in vivo, identification of specific binding residue on VDAC1, and defined downstream signaling cascade (cGAS-STING); multiple orthogonal approaches","pmids":["39934147"],"is_preprint":false},{"year":2024,"finding":"CD36 regulates CerS6 protein stability: CD36 deficiency reduces CerS6 protein expression and reduces LPS-induced inflammatory responses. CerS6-derived C16-ceramide augments LPS-induced inflammation via endoplasmic reticulum stress, activating MAPK, NF-κB, and inflammasome signaling. CerS6 protein expression and LPS-induced lethality were reduced in CD36 knockout mice.","method":"CD36 knockout mice (in vivo LPS sepsis model); CerS6 protein stability assays; ER stress markers; MAPK and NF-κB pathway analyses; inflammasome complex formation and cytokine measurement","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — CD36 KO mice with defined mechanistic readouts (ER stress, signaling pathways); CD36-CerS6 protein stability relationship established but molecular mechanism of degradation not fully characterized; single lab","pmids":["39461238"],"is_preprint":false},{"year":2022,"finding":"CerS6 protein stability is regulated by casein kinase 2α (CK2α), which phosphorylates the C-terminal region of CerS6 to increase its enzymatic activity. The herbal compound DHG promotes CerS6 protein degradation (shown by cycloheximide assay) and attenuates CK2α expression, reducing CerS6 protein levels and decreasing C16:0 ceramide in NASH rats.","method":"Cycloheximide (CHX) chase assay for CerS6 protein degradation; western blot for CK2α and CerS6 protein; RT-qPCR for mRNA; ceramide profiling by HPLC-QQQ-MS/MS in MCD diet rat model","journal":"Journal of ethnopharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — CHX assay and CK2α correlation establish post-translational regulation; mechanism of CK2α phosphorylation of CerS6 C-terminus referenced but direct phosphorylation assay not described in abstract; single lab","pmids":["35654350"],"is_preprint":false},{"year":2025,"finding":"CERS6 promotes esophageal squamous cell carcinoma (ESCC) proliferation through a non-ceramide mechanism: CERS6 sustains the stability of RPN1 (ribophorin 1) by inhibiting its ubiquitination, and downstream activation of the RPN1-IRE1-XBP1 signaling pathway reduces ER stress and ROS. ASO-mediated CERS6 targeting inhibits ESCC growth through this same pathway.","method":"CERS6 overexpression/knockdown in ESCC cells; ubiquitination assays for RPN1; IRE1-XBP1 pathway activation analysis; ROS measurement; xenograft tumor model; ASO treatment","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ubiquitination assays and pathway activation establish a novel non-ceramide mechanism; single lab, relatively recent publication","pmids":["41203639"],"is_preprint":false},{"year":2024,"finding":"CerS6 interacts directly with the mitophagy receptor BNIP3, disrupting BNIP3's binding to LC3 and thereby inhibiting mitophagy. Impaired mitochondrial clearance promotes cytoplasmic release of mtDNA and activates STING/NLRP3 signaling in AT2 cells during acute lung injury. AT2-cell-specific CerS6 knockout attenuates apoptosis, inflammation, oxidative stress, and barrier disruption in ALI mouse models.","method":"AT2-cell-specific CerS6 knockout mice (LPS and CLP models); co-immunoprecipitation of CerS6 with BNIP3; LC3-BNIP3 interaction assay; mtDNA leakage measurement; STING/NLRP3 pathway analysis; RNA-Seq","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with Co-IP establishing CerS6-BNIP3 direct interaction and defined downstream pathway; single lab, 2026 publication with 0 citations","pmids":["42159698"],"is_preprint":false},{"year":2025,"finding":"E4BP4 acts as a transcriptional repressor of Cers6 by interacting with PRDM16 and binding to a 65 kb upstream enhancer region of the Cers6 gene in brown adipose tissue, reducing CerS6 expression and C16:0 ceramide levels. E4BP4 gain-of-function prevents obesity-induced mitochondrial fragmentation and oxidative dysfunction in BAT and improves systemic glucose homeostasis independent of weight loss.","method":"E4BP4 gain-of-function in BAT; Cers6 mRNA and C16:0 ceramide measurement; PRDM16 co-immunoprecipitation with E4BP4; enhancer region binding analysis; mitochondrial morphology and function assays; metabolic phenotyping","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — gain-of-function with Co-IP and enhancer binding establishing transcriptional repression mechanism; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.05.19.652826"],"is_preprint":true},{"year":2025,"finding":"The CBX4-HDAC5-CERS6 axis regulates sphingolipid metabolism in acute myeloid leukemia: CBX4 knockdown significantly downregulates CERS6 mRNA and protein expression. CBX4 indirectly regulates CERS6 transcription by suppressing HDAC5, and dual-luciferase reporter assays confirmed that HDAC5 directly targets the CERS6 promoter region.","method":"siRNA-mediated CBX4 knockdown; dual-luciferase reporter assay (HDAC5 targeting CERS6 promoter); chromatin immunoprecipitation; ceramide measurement; RNA sequencing and proteomics in THP-1 and KG-1 cell lines","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — luciferase reporter and ChIP establish indirect HDAC5-CERS6 promoter regulation; CBX4-HDAC5 link established by knockdown; single lab","pmids":["41395279"],"is_preprint":false}],"current_model":"CERS6 encodes an ER-resident ceramide synthase with a luminal N-terminus and cytosolic C-terminus that preferentially produces C14:0 and C16:0 ceramides from sphingoid bases and acyl-CoA substrates; it is transcriptionally regulated by p53 (direct promoter binding), AKT1/FOXP3 signaling, CEBPγ (via Y-box element), the CBX4-HDAC5 axis, E4BP4/PRDM16 (in brown fat), and m6A modification (FTO-dependent mRNA stability), while its protein stability is modulated by CD36 and CK2α-mediated C-terminal phosphorylation; the resulting C16:0 ceramide drives metabolic dysfunction (obesity, insulin resistance, hypothalamic lipotoxicity) by promoting mitochondrial fragmentation and ER stress, and drives innate immune activation by binding VDAC1 to cause mtDNA leakage and cGAS-STING pathway activation, or by binding BNIP3 to inhibit PINK1/Parkin mitophagy; in cancer contexts, CerS6 forms a complex with LASP1 and actin at lamellipodia to promote RAC1-dependent cell migration and metastasis, and can also stabilize RPN1 to activate IRE1-XBP1 signaling in a ceramide-independent manner."},"narrative":{"mechanistic_narrative":"CERS6 (LASS6) encodes an endoplasmic reticulum-resident ceramide synthase that preferentially generates short-chain C14:0 and C16:0 ceramides from sphingoid bases and acyl-CoA, with its conserved Lag1/homeodomain catalytic motif oriented so the N-terminus faces the ER lumen and the C-terminus faces the cytosol [PMID:15823095, PMID:16211262]. CerS6-derived C16:0 ceramide is a central mediator of metabolic dysfunction: tissue-specific knockout in adipose and liver reduces C16:0 ceramide, increases energy expenditure, and protects against diet-induced obesity and glucose intolerance [PMID:25295788], an effect reproduced by hepatic antisense knockdown that improves insulin sensitivity in obese models [PMID:30655217], and extended to hypothalamic POMC and SF-1 neurons where CerS6 deletion preserves mitochondrial morphology and leptin sensitivity during lipotoxicity [PMID:38016943]. Mechanistically, CerS6 ceramide drives mitochondrial and ER stress to engage innate immunity and cell-death pathways: it binds VDAC1 at Glu59 to trigger mtDNA leakage and cGAS-STING activation in podocytes [PMID:39934147], binds the mitophagy receptor BNIP3 to block its LC3 interaction and provoke STING/NLRP3 signaling in alveolar epithelium [PMID:42159698], and inhibits PINK1/Parkin mitophagy to promote renal fibrosis [PMID:37458434]. In cancer, CerS6 forms a direct complex with LASP1 and actin at lamellipodia to drive RAC1-dependent migration and metastasis [PMID:32902157, PMID:37345118], and can also act ceramide-independently by stabilizing RPN1 to activate IRE1-XBP1 signaling [PMID:41203639]. CERS6 expression is controlled at multiple levels — direct p53 promoter binding [PMID:27302066], AKT1/FOXP3 [PMID:34343636], CEBPγ [PMID:33934437], and CBX4-HDAC5 [PMID:41395279] transcriptional inputs, FTO-dependent m6A mRNA stability [PMID:37734910] — and post-translationally through CK2α-mediated C-terminal phosphorylation and CD36-dependent protein stabilization [PMID:39461238, PMID:35654350].","teleology":[{"year":2005,"claim":"Established that CERS6 is a bona fide ceramide synthase with defined substrate preference and membrane topology, distinguishing it from other CerS family members.","evidence":"Overexpression with ceramide species profiling, N-glycosylation analysis, and proteinase K protection in cultured cells","pmids":["15823095"],"confidence":"High","gaps":["Substrate preference shown by overexpression, not reconstituted enzymology","Physiological tissue contexts of C14/C16 output not defined"]},{"year":2005,"claim":"Defined the gene's domain architecture, chromosomal location, and conservation, providing the molecular framework but no functional test.","evidence":"Bioinformatic genomic and phylogenetic analysis","pmids":["16211262"],"confidence":"Low","gaps":["Purely computational with no functional experiment","Tissue expression inferred in silico"]},{"year":2014,"claim":"Resolved which ceramide synthase drives obesity-associated C16:0 ceramide accumulation, placing CerS6 causally upstream of metabolic dysfunction.","evidence":"Whole-body, BAT- and liver-specific knockout mice with MS ceramide profiling and metabolic phenotyping","pmids":["25295788"],"confidence":"High","gaps":["Downstream molecular effectors of C16:0 ceramide not yet identified","Did not address neuronal or immune contributions"]},{"year":2016,"claim":"Identified CERS6 as a direct p53 transcriptional target, linking ceramide synthesis to a tumor-suppressor stress program.","evidence":"Luciferase reporters with WT vs R175H p53, in vitro IP, EMSA, and pharmacological p53 activation","pmids":["27302066"],"confidence":"High","gaps":["Cellular consequence of p53-driven CerS6 induction not fully resolved","Non-canonical response element function not validated by ChIP in vivo"]},{"year":2016,"claim":"Connected CerS6 levels to a GLUT1/WNT5A axis controlling melanoma invasion and glycolysis, indicating context-dependent tumor-suppressive behavior.","evidence":"siRNA knockdown, microarray, and GLUT1-silencing rescue in melanoma cell lines","pmids":["26934938"],"confidence":"Medium","gaps":["Single lab, cell-line only","Direct ceramide link to GLUT1 regulation not established"]},{"year":2018,"claim":"Showed CerS6 can restore chemosensitivity by promoting mitochondrial fission and apoptosis, framing it as pro-death in some cancer settings.","evidence":"Lentiviral overexpression/knockdown in cisplatin-resistant OSCC cells plus xenografts","pmids":["30054909"],"confidence":"Medium","gaps":["Mechanism linking ceramide to calpain/mitochondrial fission not defined","Single lab"]},{"year":2019,"claim":"Demonstrated CerS6 is pharmacologically actionable for metabolic disease via hepatic knockdown, corroborating genetic KO data.","evidence":"ASO knockdown in ob/ob and HFD mice with ceramide profiling and metabolic tests","pmids":["30655217"],"confidence":"High","gaps":["Tissue selectivity of ASO incomplete","Molecular mechanism of metabolic improvement not addressed here"]},{"year":2020,"claim":"Revealed a migration/metastasis function via RAC1-dependent lamellipodia, establishing a pro-tumorigenic role distinct from the metabolic axis.","evidence":"Reciprocal knockdown/overexpression in NSCLC with lung metastasis model and miR-101 luciferase analysis","pmids":["32902157"],"confidence":"High","gaps":["How ceramide alters RAC1 localization mechanistically unclear","miR-101 regulation correlative"]},{"year":2021,"claim":"Identified transcriptional inputs (CEBPγ Y-box binding) and a signaling axis (AKT1-FOXP3) that induce CERS6 in cancer.","evidence":"Promoter luciferase, ChIP, Co-IP, phosphorylation assays, and knockdowns in NSCLC and pancreatic models","pmids":["33934437","34343636"],"confidence":"Medium","gaps":["CEBPγ binding lacks ChIP confirmation","Single-lab regulatory axes not cross-validated"]},{"year":2022,"claim":"Established post-translational control of CerS6 activity and stability through CK2α phosphorylation of its cytosolic C-terminus.","evidence":"Cycloheximide chase, CK2α/CerS6 western blots, and ceramide profiling in NASH rat model","pmids":["35654350"],"confidence":"Medium","gaps":["Direct CK2α phosphorylation assay not described","Degradation machinery not identified"]},{"year":2023,"claim":"Defined CerS6 as a driver of mitochondrial/ER stress across tissues, acting through direct interaction with VDAC1, BNIP3, and PINK1 to control mtDNA leakage and mitophagy.","evidence":"Cell-type-specific KO/overexpression in podocytes and hypothalamic neurons, Co-IP, docking, and pathway readouts","pmids":["38016943","37458434","37230220","39934147","42159698"],"confidence":"High","gaps":["Ceramide-PINK1 binding supported only by docking","Whether ceramide acts directly or via membrane perturbation on each target unresolved"]},{"year":2023,"claim":"Showed CerS6 forms a direct LASP1-actin complex at lamellipodia, providing a physical mechanism for its migration function.","evidence":"Co-IP with LC-MS/MS partner identification, co-localization, reciprocal knockdowns, and C16 ceramide rescue in lung cancer cells","pmids":["37345118"],"confidence":"Medium","gaps":["LIM-domain requirement inferred not mapped","Single lab, partial ceramide rescue"]},{"year":2024,"claim":"Identified m6A (FTO) control of CerS6 mRNA stability and CD36-dependent protein stabilization, linking CerS6 to mucosal immunity and sepsis inflammation.","evidence":"FTO and CD36 conditional KO mice with MeRIP-seq, sphingolipid profiling, and inflammatory readouts","pmids":["37734910","39461238"],"confidence":"High","gaps":["Molecular mechanism of CD36-mediated stabilization not characterized","Whether S1P accumulation reflects a general CerS6-loss consequence unclear"]},{"year":2025,"claim":"Uncovered a ceramide-independent function in which CerS6 stabilizes RPN1 to activate IRE1-XBP1 signaling, plus additional transcriptional regulators (CBX4-HDAC5, E4BP4-PRDM16).","evidence":"Ubiquitination and IRE1-XBP1 assays in ESCC; luciferase/ChIP and Co-IP in AML and brown adipose models (one preprint)","pmids":["41203639","41395279","bio_10.1101_2025.05.19.652826"],"confidence":"Medium","gaps":["Non-catalytic RPN1-stabilizing mechanism single-lab","E4BP4 enhancer mechanism from preprint not peer-reviewed"]},{"year":null,"claim":"How CerS6 ceramide products are physically delivered to and recognized by distinct effector proteins (VDAC1, BNIP3, PINK1) versus acting through bulk membrane biophysics remains unresolved.","evidence":"No reconstituted system distinguishing direct ceramide-effector binding from membrane-level effects","pmids":[],"confidence":"Medium","gaps":["No structural model of CerS6 catalytic or interaction interfaces","Direct biochemical validation of ceramide-protein binding lacking for most effectors"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[18]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,19,14]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12,19]}],"complexes":[],"partners":["LASP1","VDAC1","BNIP3","RPN1","PINK1","CD36"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6ZMG9","full_name":"Ceramide synthase 6","aliases":["LAG1 longevity assurance homolog 6","Sphingoid base N-palmitoyltransferase CERS6"],"length_aa":384,"mass_kda":44.9,"function":"Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward palmitoyl-CoA (hexadecanoyl-CoA; C16:0-CoA) (PubMed:17609214, PubMed:17977534, PubMed:23530041, PubMed:26887952, PubMed:31916624, PubMed:39528795). Can use other acyl donors, but with less efficiency (PubMed:39528795). N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively (PubMed:17977534, PubMed:23530041, PubMed:26887952, PubMed:31916624). Ceramides generated by CERS6 play a role in inflammatory response (By similarity). Acts as a regulator of metabolism and hepatic lipid accumulation (By similarity). Under high fat diet, palmitoyl- (C16:0-) ceramides generated by CERS6 specifically bind the mitochondrial fission factor MFF, thereby promoting mitochondrial fragmentation and contributing to the development of obesity (By similarity)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q6ZMG9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CERS6","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000172292","cell_line_id":"CID001010","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"TMEM57","stoichiometry":10.0},{"gene":"LMAN2L","stoichiometry":4.0},{"gene":"ST7","stoichiometry":0.2},{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001010","total_profiled":1310},"omim":[{"mim_id":"619822","title":"BCL2-LIKE 13; BCL2L13","url":"https://www.omim.org/entry/619822"},{"mim_id":"615336","title":"CERAMIDE SYNTHASE 6; CERS6","url":"https://www.omim.org/entry/615336"},{"mim_id":"615335","title":"CERAMIDE SYNTHASE 5; CERS5","url":"https://www.omim.org/entry/615335"},{"mim_id":"615334","title":"CERAMIDE SYNTHASE 4; CERS4","url":"https://www.omim.org/entry/615334"},{"mim_id":"606920","title":"CERAMIDE SYNTHASE 2; CERS2","url":"https://www.omim.org/entry/606920"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CERS6"},"hgnc":{"alias_symbol":[],"prev_symbol":["LASS6"]},"alphafold":{"accession":"Q6ZMG9","domains":[{"cath_id":"1.10.10.60","chopping":"80-123","consensus_level":"high","plddt":94.5259,"start":80,"end":123},{"cath_id":"-","chopping":"129-331","consensus_level":"high","plddt":96.4705,"start":129,"end":331}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZMG9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZMG9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZMG9-F1-predicted_aligned_error_v6.png","plddt_mean":86.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CERS6","jax_strain_url":"https://www.jax.org/strain/search?query=CERS6"},"sequence":{"accession":"Q6ZMG9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6ZMG9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6ZMG9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZMG9"}},"corpus_meta":[{"pmid":"25295788","id":"PMC_25295788","title":"Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance.","date":"2014","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/25295788","citation_count":594,"is_preprint":false},{"pmid":"15823095","id":"PMC_15823095","title":"Mammalian Lass6 and its related family members regulate synthesis of specific ceramides.","date":"2005","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15823095","citation_count":336,"is_preprint":false},{"pmid":"30655217","id":"PMC_30655217","title":"The role of C16:0 ceramide in the development of obesity and type 2 diabetes: CerS6 inhibition as a novel therapeutic approach.","date":"2019","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/30655217","citation_count":162,"is_preprint":false},{"pmid":"31701672","id":"PMC_31701672","title":"Long noncoding RNA CERS6-AS1 functions as a malignancy promoter in breast cancer by binding to IGF2BP3 to enhance the stability of CERS6 mRNA.","date":"2019","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31701672","citation_count":59,"is_preprint":false},{"pmid":"37734910","id":"PMC_37734910","title":"Disruption of CerS6-mediated sphingolipid metabolism by FTO deficiency aggravates ulcerative colitis.","date":"2024","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/37734910","citation_count":48,"is_preprint":false},{"pmid":"27302066","id":"PMC_27302066","title":"CerS6 Is a Novel Transcriptional Target of p53 Protein Activated by Non-genotoxic Stress.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27302066","citation_count":45,"is_preprint":false},{"pmid":"30054909","id":"PMC_30054909","title":"CerS6 regulates cisplatin resistance in oral squamous cell carcinoma by altering mitochondrial fission and autophagy.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30054909","citation_count":42,"is_preprint":false},{"pmid":"38016943","id":"PMC_38016943","title":"CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38016943","citation_count":39,"is_preprint":false},{"pmid":"34168120","id":"PMC_34168120","title":"LncRNA CERS6-AS1 promotes proliferation and metastasis through the upregulation of YWHAG and activation of ERK signaling in pancreatic cancer.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34168120","citation_count":38,"is_preprint":false},{"pmid":"37458434","id":"PMC_37458434","title":"CERS6-derived ceramides aggravate kidney fibrosis by inhibiting PINK1-mediated mitophagy in diabetic kidney disease.","date":"2023","source":"American journal of physiology. 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The N-terminus of CERS6 faces the luminal side of the ER membrane (demonstrated by N-glycosylation of the N-terminal Asn residue), while the C-terminus faces the cytosolic side (demonstrated by proteinase K digestion assay), establishing the topology of the conserved Lag1 motif.\",\n      \"method\": \"Overexpression in cultured cells with ceramide species profiling; N-glycosylation analysis; proteinase K digestion assay; Northern blotting for tissue expression\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods (ceramide profiling, glycosylation, protease protection) in a single rigorous study establishing substrate specificity and membrane topology\",\n      \"pmids\": [\"15823095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LASS6 (CERS6) protein contains a homeodomain and LAG1 domain, maps to human chromosome 2q24.3, and is conserved in vertebrates (mouse and zebrafish orthologs identified). The gene spans ~318 kb and is broadly expressed across tissues.\",\n      \"method\": \"Bioinformatic/genomic database screening and phylogenetic analysis; in silico expression analysis\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — purely computational/bioinformatic characterization with no direct functional experiment\",\n      \"pmids\": [\"16211262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CerS6 is the ceramide synthase responsible for C16:0 ceramide production in adipose tissue and liver; whole-body and tissue-specific (BAT- and liver-specific) CerS6 knockout mice show reduced C16:0 ceramides, increased energy expenditure, and protection from high-fat-diet-induced obesity and glucose intolerance, placing CerS6-derived C16:0 ceramide as a mediator of metabolic dysfunction in obesity.\",\n      \"method\": \"Conditional knockout mouse models (whole-body, BAT-specific, liver-specific CerS6 deletion); ceramide profiling by mass spectrometry; metabolic phenotyping (glucose tolerance tests, energy expenditure measurements)\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple tissue-specific KO mouse models with ceramide profiling and metabolic phenotyping, replicated across tissue contexts in a single rigorous study\",\n      \"pmids\": [\"25295788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CerS6 is a direct transcriptional target of p53: the CerS6 promoter is activated by p53 in luciferase assays (transcriptionally inactive R175H mutant fails to activate), purified p53 binds within the CerS6 promoter (91 bp upstream to 60 bp downstream of TSS) as shown by in vitro immunoprecipitation and gel shift assays, with a single non-canonical p53 response element upstream of the TSS identified as the key binding motif. Treatment with Nutlin-3 or low-dose actinomycin D (non-genotoxic p53 activators) elevates CerS6 mRNA and protein.\",\n      \"method\": \"Luciferase reporter assays with wild-type vs. R175H p53 mutant; in vitro immunoprecipitation; electrophoretic mobility shift assay (EMSA/gel shift); pharmacological p53 activation (Nutlin-3, actinomycin D)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (luciferase, in vitro IP, gel shift, mutagenesis of p53, pharmacological validation) in a single study establishing direct p53-CerS6 promoter interaction\",\n      \"pmids\": [\"27302066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Silencing of CerS6 in melanoma cell lines increases invasion and glycolysis by upregulating GLUT1 expression, which in turn downregulates WNT5A. Silencing GLUT1 in CerS6-silenced cells restores WNT5A expression and reduces invasion/proliferation, placing CerS6 upstream of a GLUT1/WNT5A axis regulating melanoma malignancy.\",\n      \"method\": \"siRNA-mediated CerS6 knockdown; gene microarray; qPCR and western blot validation; invasion and proliferation assays; GLUT1 silencing rescue experiment\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — epistasis established by rescue experiment with GLUT1 silencing; multiple cell lines tested but single lab\",\n      \"pmids\": [\"26934938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CerS6 overexpression in cisplatin-resistant oral squamous cell carcinoma (OSCC) cells restores cisplatin sensitivity by enhancing mitochondrial fission, promoting apoptosis, and attenuating cisplatin-induced autophagy; this is associated with altered calpain expression. CerS6 knockdown has the opposite effect.\",\n      \"method\": \"Lentiviral CerS6 overexpression in resistant cells; mitochondrial morphology assessment; apoptosis assays; autophagy marker analysis; xenograft tumor model\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — gain-of-function and loss-of-function with defined cellular phenotypes (mitochondrial fission, apoptosis, autophagy) plus in vivo validation; single lab\",\n      \"pmids\": [\"30054909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Antisense oligonucleotide (ASO)-mediated knockdown of CerS6 predominantly in the liver (~90% reduction in CerS6 mRNA) reduces C16:0 ceramide levels by ~50% in liver and plasma, decreases body weight gain, reduces fat mass, lowers blood glucose (HbA1c), and improves oral glucose tolerance and insulin sensitivity in ob/ob and HFD-induced obese mouse models, confirming CerS6 as a therapeutically actionable target for hepatic C16:0 ceramide production.\",\n      \"method\": \"Antisense oligonucleotide (ASO) pharmacological knockdown in vivo; ceramide profiling; glucose and insulin tolerance tests; body composition analysis in two obese mouse models\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological knockdown in two independent disease models with ceramide profiling and metabolic phenotyping, corroborating genetic KO data from PMID 25295788\",\n      \"pmids\": [\"30655217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CERS6 is required for cell migration and invasion in non-small cell lung cancer (NSCLC): CERS6 knockdown alters the ceramide profile, suppresses RAC1-positive lamellipodia/ruffling formation, reduces cell migration in vitro, and attenuates lung metastasis in mice; forced CERS6 expression produces the opposite phenotype. CERS6 overexpression in NSCLC is driven at least in part by reduced miR-101 expression.\",\n      \"method\": \"CERS6 knockdown and overexpression in NSCLC cell lines; ceramide profiling; RAC1 localization/lamellipodia assays; in vivo lung metastasis mouse model; luciferase analysis for miR-101 regulation\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with in vitro and in vivo validation, ceramide profiling, and mechanistic pathway (RAC1/lamellipodia); single lab\",\n      \"pmids\": [\"32902157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CEBPγ transcription factor directly binds the Y-box cis-acting element in the CERS6 promoter to induce CERS6 expression, promoting ceramide-dependent lamellipodia formation and cell migration in NSCLC. YBX1 independently regulates lamellipodia and migration but without specific binding to the Y-box for CERS6 induction.\",\n      \"method\": \"Luciferase analysis of CERS6 promoter; siRNA knockdown of CEBPγ and YBX1; correlation analysis in 149 NSCLC patient database records; lamellipodia and migration assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — promoter luciferase with knockdown and phenotypic validation; single lab, no ChIP confirmation of direct binding\",\n      \"pmids\": [\"33934437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AKT1 phosphorylates FOXP3 at S418, which decreases FOXP3 binding to the CERS6 promoter and thereby induces CerS6 expression. CerS6-derived C16-ceramide produced downstream promotes accumulation of mutant p53 in pancreatic ductal adenocarcinoma. This AKT1/FOXP3 axis drives CERS6 transcription and pancreatic tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation (AKT1-FOXP3 interaction); phosphorylation assays (S418 site); chromatin immunoprecipitation (FOXP3 binding to CERS6 promoter); CerS6 overexpression/knockdown; ceramide profiling; colony formation, invasion, and tumor formation assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and phosphorylation assays establish the regulatory axis; single lab with multiple methods\",\n      \"pmids\": [\"34343636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CERS6 and LASP1 form a direct protein complex (with the LASP1 LIM domain likely required for interaction) that co-localizes on lamellipodia in lung cancer cell lines. Both CERS6 and LASP1 independently co-immunoprecipitate with actin, but these interactions are markedly reduced when the LASP1-CERS6 complex is abolished. Silencing either CERS6 or LASP1 suppresses cell migration and lamellipodia formation; ectopic addition of C16 ceramide partially rescues these phenotypes.\",\n      \"method\": \"Co-immunoprecipitation; liquid chromatography-tandem mass spectrometry (LC-MS/MS) for binding partner identification; co-localization microscopy; siRNA knockdown of CERS6 and/or LASP1; cell migration and lamellipodia formation assays; C16 ceramide rescue experiment\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with MS identification of binding partner, co-localization, reciprocal knockdowns, and ceramide rescue; single lab\",\n      \"pmids\": [\"37345118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CerS6 deficiency in hypothalamic neurons (conditional KO) attenuates HFD-induced weight gain and improves glucose metabolism. Neuron-specific CerS6 deletion in POMC-expressing cells prevents diet-induced mitochondrial morphology alterations and improves cellular leptin sensitivity, while CerS6 deletion in SF-1-expressing neurons alters feeding behavior and alleviates adverse metabolic effects. CerS6-derived ceramides promote ER/mitochondrial stress in hypothalamic lipotoxicity.\",\n      \"method\": \"Conditional neuronal CerS6 knockout mice (POMC-Cre and SF-1-Cre drivers); mitochondrial morphology analysis; leptin sensitivity assays; metabolic phenotyping (glucose tolerance, insulin sensitivity, body weight, food intake); palmitate treatment of cultured hypothalamic neurons in vitro\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with multiple mechanistic readouts (mitochondrial morphology, leptin signaling, ER stress) across two distinct neuron populations; rigorous in vivo study\",\n      \"pmids\": [\"38016943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CERS6-derived C16:0 ceramide (and C14:0 ceramide) inhibit PINK1-mediated mitophagy in renal tubular epithelial cells, likely by binding directly to the PINK1 protein (supported by automated docking analysis). CerS6 deficiency in db/db diabetic mice restores PINK1/Parkin-mediated mitophagy, reduces damaged mitochondria, and attenuates interstitial fibrosis. Inhibiting PINK1 in CERS6-knockdown HK-2 cells abolishes the protective effect.\",\n      \"method\": \"CerS6 knockout in db/db mice; ceramide profiling (LC-MS/MS); mitophagy assays (PINK1/Parkin pathway markers); CERS6 knockdown in HK-2 cells with PINK1 inhibition rescue; automated molecular docking of ceramides to PINK1\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vivo KO with mitophagy readouts and epistasis via PINK1 inhibition rescue; direct ceramide-PINK1 binding supported only by docking (not biochemically validated)\",\n      \"pmids\": [\"37458434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"High glucose promotes CerS6 synthesis through the TLR4/IKKβ signaling pathway in human liver (LO2) cells. CerS6-derived ceramide promotes mitochondrial oxidative stress (mtROS), and CerS6 knockout attenuates mitochondrial oxidative stress, inhibits ferroptosis, and ameliorates markers of liver injury and fibrosis under high-glucose conditions.\",\n      \"method\": \"Pharmacological TLR4/IKKβ pathway manipulation; CerS6 knockdown and overexpression in LO2 cells; mitochondrial ROS measurement; ferroptosis marker analysis; Mito-TEMPO antioxidant intervention\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pathway epistasis via pharmacological inhibition and rescue, with KO/OE and mechanistic readouts; single lab, in vitro\",\n      \"pmids\": [\"37230220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FTO (m6A demethylase) deficiency increases m6A modification on CerS6 mRNA, decreasing its stability and reducing CerS6 expression in intestinal epithelial cells. Reduced CerS6 leads to S1P accumulation, which triggers proinflammatory macrophage activation (secreting SAA1/3) and ultimately induces Th17 cell differentiation, aggravating ulcerative colitis.\",\n      \"method\": \"Conditional FTO knockout mice (Villin-Cre); RNA and methylated RNA immunoprecipitation sequencing (MeRIP-seq); ceramide/S1P profiling by LC-MS; macrophage conditioned medium treatment; real-time PCR and 16S rRNA sequencing\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO combined with MeRIP-seq establishing the m6A-CerS6 mRNA stability mechanism, ceramide/S1P profiling, and immune cell functional readouts; multiple orthogonal methods\",\n      \"pmids\": [\"37734910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CerS6-derived ceramide (d18:1/16:0) binds to the mitochondrial channel protein VDAC1 at Glu59, initiating mitochondrial DNA (mtDNA) leakage, activating the cGAS-STING signaling pathway, and promoting inflammatory responses in kidney podocytes in diabetic kidney disease. Podocyte-specific CerS6 knockout ameliorates glomerular injury and inflammation, while podocyte-specific CerS6 overexpression induces proteinuria.\",\n      \"method\": \"Podocyte-specific CerS6 knockout and overexpression in diabetic mice; ceramide-VDAC1 binding analysis (including identification of Glu59 residue); mtDNA leakage assays; cGAS-STING pathway activation measurement; histology and proteinuria assessment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific gain and loss of function in vivo, identification of specific binding residue on VDAC1, and defined downstream signaling cascade (cGAS-STING); multiple orthogonal approaches\",\n      \"pmids\": [\"39934147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD36 regulates CerS6 protein stability: CD36 deficiency reduces CerS6 protein expression and reduces LPS-induced inflammatory responses. CerS6-derived C16-ceramide augments LPS-induced inflammation via endoplasmic reticulum stress, activating MAPK, NF-κB, and inflammasome signaling. CerS6 protein expression and LPS-induced lethality were reduced in CD36 knockout mice.\",\n      \"method\": \"CD36 knockout mice (in vivo LPS sepsis model); CerS6 protein stability assays; ER stress markers; MAPK and NF-κB pathway analyses; inflammasome complex formation and cytokine measurement\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — CD36 KO mice with defined mechanistic readouts (ER stress, signaling pathways); CD36-CerS6 protein stability relationship established but molecular mechanism of degradation not fully characterized; single lab\",\n      \"pmids\": [\"39461238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CerS6 protein stability is regulated by casein kinase 2α (CK2α), which phosphorylates the C-terminal region of CerS6 to increase its enzymatic activity. The herbal compound DHG promotes CerS6 protein degradation (shown by cycloheximide assay) and attenuates CK2α expression, reducing CerS6 protein levels and decreasing C16:0 ceramide in NASH rats.\",\n      \"method\": \"Cycloheximide (CHX) chase assay for CerS6 protein degradation; western blot for CK2α and CerS6 protein; RT-qPCR for mRNA; ceramide profiling by HPLC-QQQ-MS/MS in MCD diet rat model\",\n      \"journal\": \"Journal of ethnopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — CHX assay and CK2α correlation establish post-translational regulation; mechanism of CK2α phosphorylation of CerS6 C-terminus referenced but direct phosphorylation assay not described in abstract; single lab\",\n      \"pmids\": [\"35654350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CERS6 promotes esophageal squamous cell carcinoma (ESCC) proliferation through a non-ceramide mechanism: CERS6 sustains the stability of RPN1 (ribophorin 1) by inhibiting its ubiquitination, and downstream activation of the RPN1-IRE1-XBP1 signaling pathway reduces ER stress and ROS. ASO-mediated CERS6 targeting inhibits ESCC growth through this same pathway.\",\n      \"method\": \"CERS6 overexpression/knockdown in ESCC cells; ubiquitination assays for RPN1; IRE1-XBP1 pathway activation analysis; ROS measurement; xenograft tumor model; ASO treatment\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ubiquitination assays and pathway activation establish a novel non-ceramide mechanism; single lab, relatively recent publication\",\n      \"pmids\": [\"41203639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CerS6 interacts directly with the mitophagy receptor BNIP3, disrupting BNIP3's binding to LC3 and thereby inhibiting mitophagy. Impaired mitochondrial clearance promotes cytoplasmic release of mtDNA and activates STING/NLRP3 signaling in AT2 cells during acute lung injury. AT2-cell-specific CerS6 knockout attenuates apoptosis, inflammation, oxidative stress, and barrier disruption in ALI mouse models.\",\n      \"method\": \"AT2-cell-specific CerS6 knockout mice (LPS and CLP models); co-immunoprecipitation of CerS6 with BNIP3; LC3-BNIP3 interaction assay; mtDNA leakage measurement; STING/NLRP3 pathway analysis; RNA-Seq\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with Co-IP establishing CerS6-BNIP3 direct interaction and defined downstream pathway; single lab, 2026 publication with 0 citations\",\n      \"pmids\": [\"42159698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"E4BP4 acts as a transcriptional repressor of Cers6 by interacting with PRDM16 and binding to a 65 kb upstream enhancer region of the Cers6 gene in brown adipose tissue, reducing CerS6 expression and C16:0 ceramide levels. E4BP4 gain-of-function prevents obesity-induced mitochondrial fragmentation and oxidative dysfunction in BAT and improves systemic glucose homeostasis independent of weight loss.\",\n      \"method\": \"E4BP4 gain-of-function in BAT; Cers6 mRNA and C16:0 ceramide measurement; PRDM16 co-immunoprecipitation with E4BP4; enhancer region binding analysis; mitochondrial morphology and function assays; metabolic phenotyping\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — gain-of-function with Co-IP and enhancer binding establishing transcriptional repression mechanism; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.19.652826\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The CBX4-HDAC5-CERS6 axis regulates sphingolipid metabolism in acute myeloid leukemia: CBX4 knockdown significantly downregulates CERS6 mRNA and protein expression. CBX4 indirectly regulates CERS6 transcription by suppressing HDAC5, and dual-luciferase reporter assays confirmed that HDAC5 directly targets the CERS6 promoter region.\",\n      \"method\": \"siRNA-mediated CBX4 knockdown; dual-luciferase reporter assay (HDAC5 targeting CERS6 promoter); chromatin immunoprecipitation; ceramide measurement; RNA sequencing and proteomics in THP-1 and KG-1 cell lines\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — luciferase reporter and ChIP establish indirect HDAC5-CERS6 promoter regulation; CBX4-HDAC5 link established by knockdown; single lab\",\n      \"pmids\": [\"41395279\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CERS6 encodes an ER-resident ceramide synthase with a luminal N-terminus and cytosolic C-terminus that preferentially produces C14:0 and C16:0 ceramides from sphingoid bases and acyl-CoA substrates; it is transcriptionally regulated by p53 (direct promoter binding), AKT1/FOXP3 signaling, CEBPγ (via Y-box element), the CBX4-HDAC5 axis, E4BP4/PRDM16 (in brown fat), and m6A modification (FTO-dependent mRNA stability), while its protein stability is modulated by CD36 and CK2α-mediated C-terminal phosphorylation; the resulting C16:0 ceramide drives metabolic dysfunction (obesity, insulin resistance, hypothalamic lipotoxicity) by promoting mitochondrial fragmentation and ER stress, and drives innate immune activation by binding VDAC1 to cause mtDNA leakage and cGAS-STING pathway activation, or by binding BNIP3 to inhibit PINK1/Parkin mitophagy; in cancer contexts, CerS6 forms a complex with LASP1 and actin at lamellipodia to promote RAC1-dependent cell migration and metastasis, and can also stabilize RPN1 to activate IRE1-XBP1 signaling in a ceramide-independent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CERS6 (LASS6) encodes an endoplasmic reticulum-resident ceramide synthase that preferentially generates short-chain C14:0 and C16:0 ceramides from sphingoid bases and acyl-CoA, with its conserved Lag1/homeodomain catalytic motif oriented so the N-terminus faces the ER lumen and the C-terminus faces the cytosol [#0, #1]. CerS6-derived C16:0 ceramide is a central mediator of metabolic dysfunction: tissue-specific knockout in adipose and liver reduces C16:0 ceramide, increases energy expenditure, and protects against diet-induced obesity and glucose intolerance [#2], an effect reproduced by hepatic antisense knockdown that improves insulin sensitivity in obese models [#6], and extended to hypothalamic POMC and SF-1 neurons where CerS6 deletion preserves mitochondrial morphology and leptin sensitivity during lipotoxicity [#11]. Mechanistically, CerS6 ceramide drives mitochondrial and ER stress to engage innate immunity and cell-death pathways: it binds VDAC1 at Glu59 to trigger mtDNA leakage and cGAS-STING activation in podocytes [#15], binds the mitophagy receptor BNIP3 to block its LC3 interaction and provoke STING/NLRP3 signaling in alveolar epithelium [#19], and inhibits PINK1/Parkin mitophagy to promote renal fibrosis [#12]. In cancer, CerS6 forms a direct complex with LASP1 and actin at lamellipodia to drive RAC1-dependent migration and metastasis [#7, #10], and can also act ceramide-independently by stabilizing RPN1 to activate IRE1-XBP1 signaling [#18]. CERS6 expression is controlled at multiple levels — direct p53 promoter binding [#3], AKT1/FOXP3 [#9], CEBPγ [#8], and CBX4-HDAC5 [#21] transcriptional inputs, FTO-dependent m6A mRNA stability [#14] — and post-translationally through CK2α-mediated C-terminal phosphorylation and CD36-dependent protein stabilization [#16, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that CERS6 is a bona fide ceramide synthase with defined substrate preference and membrane topology, distinguishing it from other CerS family members.\",\n      \"evidence\": \"Overexpression with ceramide species profiling, N-glycosylation analysis, and proteinase K protection in cultured cells\",\n      \"pmids\": [\"15823095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate preference shown by overexpression, not reconstituted enzymology\", \"Physiological tissue contexts of C14/C16 output not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the gene's domain architecture, chromosomal location, and conservation, providing the molecular framework but no functional test.\",\n      \"evidence\": \"Bioinformatic genomic and phylogenetic analysis\",\n      \"pmids\": [\"16211262\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely computational with no functional experiment\", \"Tissue expression inferred in silico\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved which ceramide synthase drives obesity-associated C16:0 ceramide accumulation, placing CerS6 causally upstream of metabolic dysfunction.\",\n      \"evidence\": \"Whole-body, BAT- and liver-specific knockout mice with MS ceramide profiling and metabolic phenotyping\",\n      \"pmids\": [\"25295788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream molecular effectors of C16:0 ceramide not yet identified\", \"Did not address neuronal or immune contributions\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified CERS6 as a direct p53 transcriptional target, linking ceramide synthesis to a tumor-suppressor stress program.\",\n      \"evidence\": \"Luciferase reporters with WT vs R175H p53, in vitro IP, EMSA, and pharmacological p53 activation\",\n      \"pmids\": [\"27302066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequence of p53-driven CerS6 induction not fully resolved\", \"Non-canonical response element function not validated by ChIP in vivo\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected CerS6 levels to a GLUT1/WNT5A axis controlling melanoma invasion and glycolysis, indicating context-dependent tumor-suppressive behavior.\",\n      \"evidence\": \"siRNA knockdown, microarray, and GLUT1-silencing rescue in melanoma cell lines\",\n      \"pmids\": [\"26934938\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, cell-line only\", \"Direct ceramide link to GLUT1 regulation not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed CerS6 can restore chemosensitivity by promoting mitochondrial fission and apoptosis, framing it as pro-death in some cancer settings.\",\n      \"evidence\": \"Lentiviral overexpression/knockdown in cisplatin-resistant OSCC cells plus xenografts\",\n      \"pmids\": [\"30054909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking ceramide to calpain/mitochondrial fission not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated CerS6 is pharmacologically actionable for metabolic disease via hepatic knockdown, corroborating genetic KO data.\",\n      \"evidence\": \"ASO knockdown in ob/ob and HFD mice with ceramide profiling and metabolic tests\",\n      \"pmids\": [\"30655217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue selectivity of ASO incomplete\", \"Molecular mechanism of metabolic improvement not addressed here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a migration/metastasis function via RAC1-dependent lamellipodia, establishing a pro-tumorigenic role distinct from the metabolic axis.\",\n      \"evidence\": \"Reciprocal knockdown/overexpression in NSCLC with lung metastasis model and miR-101 luciferase analysis\",\n      \"pmids\": [\"32902157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ceramide alters RAC1 localization mechanistically unclear\", \"miR-101 regulation correlative\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified transcriptional inputs (CEBPγ Y-box binding) and a signaling axis (AKT1-FOXP3) that induce CERS6 in cancer.\",\n      \"evidence\": \"Promoter luciferase, ChIP, Co-IP, phosphorylation assays, and knockdowns in NSCLC and pancreatic models\",\n      \"pmids\": [\"33934437\", \"34343636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CEBPγ binding lacks ChIP confirmation\", \"Single-lab regulatory axes not cross-validated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established post-translational control of CerS6 activity and stability through CK2α phosphorylation of its cytosolic C-terminus.\",\n      \"evidence\": \"Cycloheximide chase, CK2α/CerS6 western blots, and ceramide profiling in NASH rat model\",\n      \"pmids\": [\"35654350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CK2α phosphorylation assay not described\", \"Degradation machinery not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined CerS6 as a driver of mitochondrial/ER stress across tissues, acting through direct interaction with VDAC1, BNIP3, and PINK1 to control mtDNA leakage and mitophagy.\",\n      \"evidence\": \"Cell-type-specific KO/overexpression in podocytes and hypothalamic neurons, Co-IP, docking, and pathway readouts\",\n      \"pmids\": [\"38016943\", \"37458434\", \"37230220\", \"39934147\", \"42159698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ceramide-PINK1 binding supported only by docking\", \"Whether ceramide acts directly or via membrane perturbation on each target unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed CerS6 forms a direct LASP1-actin complex at lamellipodia, providing a physical mechanism for its migration function.\",\n      \"evidence\": \"Co-IP with LC-MS/MS partner identification, co-localization, reciprocal knockdowns, and C16 ceramide rescue in lung cancer cells\",\n      \"pmids\": [\"37345118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LIM-domain requirement inferred not mapped\", \"Single lab, partial ceramide rescue\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified m6A (FTO) control of CerS6 mRNA stability and CD36-dependent protein stabilization, linking CerS6 to mucosal immunity and sepsis inflammation.\",\n      \"evidence\": \"FTO and CD36 conditional KO mice with MeRIP-seq, sphingolipid profiling, and inflammatory readouts\",\n      \"pmids\": [\"37734910\", \"39461238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of CD36-mediated stabilization not characterized\", \"Whether S1P accumulation reflects a general CerS6-loss consequence unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a ceramide-independent function in which CerS6 stabilizes RPN1 to activate IRE1-XBP1 signaling, plus additional transcriptional regulators (CBX4-HDAC5, E4BP4-PRDM16).\",\n      \"evidence\": \"Ubiquitination and IRE1-XBP1 assays in ESCC; luciferase/ChIP and Co-IP in AML and brown adipose models (one preprint)\",\n      \"pmids\": [\"41203639\", \"41395279\", \"bio_10.1101_2025.05.19.652826\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-catalytic RPN1-stabilizing mechanism single-lab\", \"E4BP4 enhancer mechanism from preprint not peer-reviewed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CerS6 ceramide products are physically delivered to and recognized by distinct effector proteins (VDAC1, BNIP3, PINK1) versus acting through bulk membrane biophysics remains unresolved.\",\n      \"evidence\": \"No reconstituted system distinguishing direct ceramide-effector binding from membrane-level effects\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CerS6 catalytic or interaction interfaces\", \"Direct biochemical validation of ceramide-protein binding lacking for most effectors\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 19, 14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LASP1\", \"VDAC1\", \"BNIP3\", \"RPN1\", \"PINK1\", \"CD36\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}