{"gene":"HSPA12A","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2019,"finding":"HSPA12A selectively binds to the cytoplasmic domain of SorLA (but not Sortilin) in an ADP/ATP-dependent manner, mediated by specific acidic residues in SorLA's cytosolic domain, and this interaction affects both endocytic speed and subcellular localization of SorLA. This is the first described substrate/binding partner of HSPA12A.","method":"Co-immunoprecipitation/pulldown, ADP/ATP-dependent binding assay, site-directed mutagenesis of SorLA acidic residues, subcellular localization assay, endocytosis assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assay with mechanistic mutagenesis, single lab with multiple orthogonal methods but no independent replication","pmids":["30679749"],"is_preprint":false},{"year":2020,"finding":"HSPA12A directly interacts with PGC-1α in hepatocytes and increases its nuclear translocation, thereby inducing AOAH (acyloxyacyl hydrolase) expression, which inactivates cytosolic LPS and inhibits Caspase-11-mediated gasdermin D cleavage (pyroptosis) during sepsis-induced liver injury.","method":"Immunoprecipitation (direct protein interaction), loss- and gain-of-function studies (Hspa12a-/- mice and overexpression), immunoblotting for Caspase-11 and GSDMD cleavage, AOAH overexpression rescue experiment","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing direct interaction, genetic KO mouse model, rescue experiments with AOAH overexpression, multiple orthogonal methods in one study","pmids":["32332915"],"is_preprint":false},{"year":2018,"finding":"HSPA12A interacts with the M2 isoform of pyruvate kinase (PKM2) in macrophages and promotes its nuclear translocation, thereby driving M1 macrophage polarization and secretion of pro-inflammatory cytokines, which in turn cause hepatocyte steatosis via paracrine effects in NASH.","method":"Immunoprecipitation (HSPA12A–PKM2 interaction), loss- and gain-of-function in macrophages, nuclear fractionation, Hspa12a-/- mice on high-fat diet, paracrine co-culture assays","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP establishing direct interaction, genetic KO mouse model, multiple functional readouts and rescue experiments, single lab with multiple orthogonal methods","pmids":["30455376"],"is_preprint":false},{"year":2019,"finding":"HSPA12A is required for adipocyte differentiation through a positive feedback loop with PPARγ: PPARγ directly binds the PPAR response element in the Hspa12a promoter (confirmed by ChIP), activating HSPA12A expression, while HSPA12A in turn promotes PPARγ expression and adipogenic gene transcription during differentiation.","method":"Chromatin immunoprecipitation (ChIP) for PPARγ binding to Hspa12a promoter, Hspa12a-/- mouse model (high-fat diet), PPARγ inhibitor (GW9662) rescue, loss- and gain-of-function in primary adipocyte precursors","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP establishes direct transcriptional regulation, KO mouse phenotype, pharmacological rescue, multiple orthogonal methods in single lab","pmids":["30742088"],"is_preprint":false},{"year":2020,"finding":"HSPA12A in renal cell carcinoma (RCC) cells interacts with HRD1 ubiquitin E3 ligase and promotes ubiquitin-proteasome degradation of CD147, thereby reducing lactate export and glycolysis, and suppressing RCC cell migration. CD147 overexpression abolishes HSPA12A's inhibitory effects on lactate export and migration.","method":"Mass spectrometry (interactome), immunoprecipitation (HSPA12A–HRD1 interaction), cycloheximide chase and MG132 proteasome inhibitor assays (protein stability), CD147 overexpression rescue, Transwell migration and wound healing assays, Seahorse glycolysis assay","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-identified interaction confirmed by Co-IP, proteasome degradation mechanism validated with multiple pharmacological tools, rescue experiment, multiple orthogonal methods in single lab","pmids":["32754264"],"is_preprint":false},{"year":2021,"finding":"HSPA12A overexpression in endothelial cells protects against LPS-induced endothelial hyperpermeability and death by activating ERKs and Akt phosphorylation; pharmacological inhibition of either ERKs or Akt abolished HSPA12A's protective effects. HSPA12A also upregulated VE-cadherin and downregulated VEGF expression.","method":"HSPA12A overexpression in HUVECs, Hspa12a-/- mouse model (LPS-induced ALI), ERK/Akt inhibitor treatment, immunoblotting for phosphorylation, permeability assay, cell death assay","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model plus in vitro gain-of-function with pharmacological inhibitor rescue, single lab","pmids":["34343936"],"is_preprint":false},{"year":2022,"finding":"HSPA12A promotes angiogenesis in endothelial cells by activating p38 and ERK phosphorylation, leading to increased AP-1 phosphorylation and nuclear localization, which drives expression of VEGF, VEGFR2, and Ang-1. Inhibition of p38 or ERKs abolished HSPA12A-promoted AP-1 activation and angiogenic characteristics.","method":"HSPA12A overexpression/deficiency in endothelial cells, Hspa12a-/- mouse MI model, p38/ERK inhibitor pharmacological rescue, immunoblotting for phosphorylation, nuclear fractionation, tube formation/migration/proliferation assays, echocardiography","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with defined MI phenotype plus in vitro pathway dissection with pharmacological inhibitors, single lab","pmids":["35783189"],"is_preprint":false},{"year":2022,"finding":"SRSF11 directly binds a motif in exon 2 of HSPA12A pre-mRNA (confirmed by CLIP and mini-gene assay) and promotes exon 2 skipping; the HSPA12A transcript retaining exon 2 increases N-cadherin expression by enhancing RNA stability, thereby promoting colorectal cancer metastasis. PAK5 phosphorylates SRSF11 at serine 287 to protect it from ubiquitination, maintaining SRSF11-mediated HSPA12A splicing regulation.","method":"UV crosslinking and immunoprecipitation (CLIP), mini-gene reporter assay, RNA-seq, in vitro kinase assay (PAK5 phosphorylates SRSF11), Co-IP, Phospho-tag SDS-PAGE, RNA stability assay","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CLIP establishes direct RNA-protein interaction, mini-gene validates splicing, in vitro kinase assay validates phosphorylation; single lab","pmids":["36394206"],"is_preprint":false},{"year":2023,"finding":"Hepatocyte HSPA12A overexpression reduces glycolysis-generated lactate, thereby decreasing HMGB1 lactylation and secretion from hepatocytes during liver ischemia/reperfusion (LI/R); HMGB1 knockdown reversed the deleterious effects of HSPA12A knockout on macrophage chemotaxis and inflammatory activation, placing HSPA12A upstream of glycolysis → lactate → HMGB1 lactylation → macrophage recruitment in LI/R injury.","method":"Hepatocyte-specific HSPA12A overexpression (in vivo), Hspa12a-/- mice, HMGB1 knockdown rescue, immunoprecipitation for HMGB1 lactylation, Transwell chemotaxis assay, exosome HMGB1 quantification, ALT/AST assays","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — hepatocyte-specific overexpression and KO mouse models, HMGB1 lactylation confirmed by Co-IP, genetic rescue with HMGB1 knockdown, multiple orthogonal methods in single study","pmids":["37441587"],"is_preprint":false},{"year":2023,"finding":"HSPA12A in hippocampal neurons inhibits GSK3β to sustain glycolytic enzyme expression and lactate production; Hspa12a-/- mice show decreased CSF lactate, impaired adult hippocampal neurogenesis, and mood instability behaviors, all of which are rescued by lactate administration, establishing HSPA12A as a regulator of cerebral lactate homeostasis via GSK3β inhibition.","method":"Hspa12a-/- mouse behavioral tests (open field, forced swimming, elevated plus maze, sucrose preference), BrdU neurogenesis labeling, CSF lactate measurement, HSPA12A overexpression in primary hippocampal neurons (glycolysis readout), lactate rescue administration","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with multiple behavioral readouts, lactate rescue establishes pathway position, single lab; GSK3β inhibition mechanism is less directly validated","pmids":["37580315"],"is_preprint":false},{"year":2024,"finding":"HSPA12A acts as a scaffolding protein in cardiac fibroblasts by binding both p53 and USP10 (ubiquitin-specific protease 10) simultaneously, thereby promoting USP10-mediated deubiquitination and stabilization of p53 protein, which in turn inhibits glycolysis and prevents cardiac fibroblast activation into myofibroblasts; Hspa12a-/- mice showed exacerbated cardiac fibrosis post-MI.","method":"Immunoprecipitation-immunoblotting (HSPA12A–p53 and HSPA12A–USP10 interactions), cycloheximide and MG132 stability assays, Hspa12a-/- mouse MI model, Masson/picrosirius staining for fibrosis, echocardiography, primary cardiac fibroblast loss/gain-of-function","journal":"Journal of advanced research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP establishes ternary scaffolding complex, protein stability validated by multiple pharmacological tools, KO mouse phenotype, multiple orthogonal methods in single study","pmids":["38219869"],"is_preprint":false},{"year":2024,"finding":"In cardiomyocytes, HSPA12A maintains aerobic glycolysis during reperfusion by increasing Smurf1-mediated HIF1α protein stability, which upregulates glycolytic gene expression and sustains H3 (Histone 3) lactylation as an epigenetic mechanism supporting cardiomyocyte survival; Hspa12a-/- mice showed exacerbated aerobic glycolysis decrease and worse MI/R injury.","method":"Hspa12a-/- mouse MI/R model, gain- and loss-of-function in cardiomyocytes, glycolytic flux measurement, H3 lactylation assay (epigenetic readout), HIF1α protein stability assay, Smurf1-dependent mechanism analysis, echocardiography","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with defined cardiac phenotype, multiple mechanistic layers assessed, single lab; Smurf1–HIF1α mechanism described but direct HSPA12A–Smurf1 interaction evidence limited to abstract summary","pmids":["38421727"],"is_preprint":false},{"year":2024,"finding":"HSPA12A directly interacts with c-Myc in renal tubular epithelial cells and enhances its nuclear localization; HSPA12A also promotes glycolysis-derived lactate generation in a HIF1α-dependent manner, increasing c-Myc lactylation, which further enhances c-Myc nuclear localization and transcription of proliferation-related genes to support TEC proliferation after KI/R; inhibiting c-Myc lactylation abolished HSPA12A-induced proliferation.","method":"Co-immunoprecipitation (HSPA12A–c-Myc direct interaction), c-Myc lactylation assay, pharmacological inhibition of c-Myc lactylation, nuclear fractionation, gain-of-function HSPA12A overexpression, HIF1α-dependent mechanism analysis, Hspa12a-/- mouse KI/R model","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes direct HSPA12A–c-Myc interaction, lactylation inhibitor rescue validates mechanism, KO mouse model; single lab","pmids":["39277835"],"is_preprint":false},{"year":2024,"finding":"In cardiomyocytes during sepsis, HSPA12A overexpression activates mTOR and inhibits autophagy, thereby enhancing TLR4/MyD88/NF-κB-mediated inflammation; conversely, HSPA12A knockout attenuated sepsis-induced cardiomyocyte death and cardiac dysfunction. Rapamycin (mTOR inhibitor) abolished the HSPA12A-induced autophagy inhibition and inflammation, placing HSPA12A upstream of mTOR-autophagy in the septic cardiomyopathy pathway.","method":"Hspa12a-/- mouse CLP sepsis model, HSPA12A overexpression in primary cardiomyocytes, rapamycin pharmacological rescue, LC3-II/p62 autophagy markers, NF-κB pathway immunoblotting, TUNEL/PI death staining, echocardiography","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with defined cardiac sepsis phenotype, pharmacological mTOR inhibitor rescue validates pathway, single lab","pmids":["39642573"],"is_preprint":false},{"year":2021,"finding":"HSPA12A downregulation during bupivacaine-induced myotoxicity underlies mitochondrial damage in skeletal muscle; HSPA12A overexpression attenuated bupivacaine-induced cell death, restored glucose consumption and ATP production, reduced mitochondrial fragmentation, and maintained PGC1α expression and nuclear localization. Pharmacological inhibition of PGC1α (SR-18292) abolished HSPA12A-mediated protection, placing HSPA12A upstream of PGC1α-mediated mitochondrial integrity.","method":"HSPA12A overexpression in C2C12 myoblasts, PGC1α inhibitor (SR-18292) rescue, mitochondrial content and morphology assay, ATP production assay, PGC1α nuclear fractionation, Bupivacaine in vivo mouse model","journal":"Toxicology and applied pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function plus pharmacological rescue establishes pathway, in vitro and in vivo data, single lab; no direct HSPA12A–PGC1α binding shown in this paper (interaction established in PMID:32332915)","pmids":["34793778"],"is_preprint":false},{"year":2024,"finding":"HSPA12A promotes HIF1α protein stability through a Smurf1-dependent mechanism in renal tubular epithelial cells (HK-2) after hypoxia/reoxygenation, independently of HIF1α transcription; HIF1α pharmacological inhibition (YC-1) abolished HSPA12A-promoted glycolytic flux and cell proliferation, confirming HSPA12A acts through Smurf1→HIF1α→glycolysis to support TEC proliferation.","method":"HSPA12A gain- and loss-of-function in HK-2 cells, HIF1α inhibitor (YC-1), cycloheximide protein stability assay, qPCR (HIF1α transcription vs. protein), glycolysis inhibitors (2-DG, oxamate), proliferation assay","journal":"Cell stress & chaperones","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological inhibitors dissect pathway, protein stability vs. transcription distinguished; single lab, in vitro only","pmids":["39349238"],"is_preprint":false}],"current_model":"HSPA12A is an atypical HSP70-family member that functions primarily as a scaffolding/chaperone-like protein rather than a classical chaperone: it directly binds partners including PGC-1α, PKM2, p53/USP10, HRD1, c-Myc, and the SorLA cytoplasmic domain to modulate their nuclear translocation, ubiquitin-proteasome stability, or subcellular trafficking; in parallel, it sustains aerobic glycolysis (via Smurf1-HIF1α stabilization and GSK3β inhibition) to regulate lactate production, protein lactylation (HMGB1, c-Myc, H3), and downstream transcriptional programs, thereby controlling diverse cell-type-specific processes including hepatocyte pyroptosis, macrophage M1 polarization, adipocyte differentiation, cardiac fibroblast activation, endothelial barrier integrity, angiogenesis, and renal tubular cell proliferation."},"narrative":{"mechanistic_narrative":"HSPA12A is an atypical HSP70-family protein that acts as a scaffold and trafficking/stability modulator for diverse partner proteins and, in parallel, sustains aerobic glycolysis to drive lactate-dependent signaling and epigenetic programs across multiple cell types [PMID:32332915, PMID:37441587]. As a binding protein, it engages partners in an ADP/ATP-dependent manner—first shown for the SorLA cytoplasmic domain, where binding controls SorLA endocytic speed and subcellular localization [PMID:30679749]—and it directs the nuclear translocation of transcriptional and metabolic regulators including PGC-1α in hepatocytes and skeletal muscle [PMID:32332915, PMID:34793778], PKM2 in macrophages [PMID:30455376], and c-Myc in renal tubular cells [PMID:39277835]. HSPA12A also governs protein stability through ubiquitin-pathway components: it recruits the HRD1 E3 ligase to drive proteasomal degradation of CD147 [PMID:32754264], and it forms a ternary complex with p53 and USP10 that promotes USP10-mediated deubiquitination and stabilization of p53 [PMID:38219869]. A recurrent theme is metabolic control: HSPA12A increases Smurf1-dependent HIF1α protein stability and inhibits GSK3β to sustain glycolytic gene expression and lactate output [PMID:38421727, PMID:39349238, PMID:37580315], and the resulting lactate fuels lactylation of HMGB1, c-Myc, and histone H3 to regulate downstream inflammatory, proliferative, and survival programs [PMID:37441587, PMID:39277835, PMID:38421727]. Through these activities HSPA12A controls cell-type-specific outcomes including hepatocyte pyroptosis [PMID:32332915], macrophage M1 polarization [PMID:30455376], adipocyte differentiation via a PPARγ feedback loop [PMID:30742088], cardiac fibroblast activation [PMID:38219869], endothelial barrier integrity and angiogenesis [PMID:34343936, PMID:35783189], and renal tubular cell proliferation [PMID:39277835, PMID:39349238]. Its own expression is regulated transcriptionally by PPARγ [PMID:30742088] and post-transcriptionally by SRSF11-mediated exon 2 splicing [PMID:36394206].","teleology":[{"year":2018,"claim":"Established the first functional link between HSPA12A and metabolic-transcriptional reprogramming by showing it controls nuclear translocation of a partner protein.","evidence":"Co-IP, nuclear fractionation, and Hspa12a-/- mice in macrophages identifying HSPA12A–PKM2 interaction driving M1 polarization in NASH","pmids":["30455376"],"confidence":"High","gaps":["Mechanism by which HSPA12A enhances PKM2 nuclear import not defined","Direct binding interface unmapped"]},{"year":2019,"claim":"Identified the first direct binding partner of HSPA12A and showed binding is nucleotide-dependent, framing it as an HSP70-like scaffold acting on cargo trafficking.","evidence":"Reciprocal Co-IP/pulldown with ADP/ATP-dependent binding assays and SorLA acidic-residue mutagenesis, plus endocytosis assays","pmids":["30679749"],"confidence":"Medium","gaps":["No independent replication","Selectivity for SorLA over Sortilin mechanistically unexplained","No structural model of the interaction"]},{"year":2019,"claim":"Placed HSPA12A within a transcriptional feedback circuit by establishing both that PPARγ directly drives its expression and that it is required for adipogenesis.","evidence":"ChIP for PPARγ binding to the Hspa12a promoter, Hspa12a-/- mice, and GW9662 pharmacological rescue in primary adipocyte precursors","pmids":["30742088"],"confidence":"High","gaps":["Molecular mechanism by which HSPA12A promotes PPARγ expression unresolved"]},{"year":2020,"claim":"Demonstrated HSPA12A directly binds PGC-1α and routes it to the nucleus to suppress hepatocyte pyroptosis, generalizing the nuclear-translocation scaffold model to a protective metabolic regulator.","evidence":"Reciprocal Co-IP, Hspa12a-/- mice, and AOAH overexpression rescue measuring Caspase-11/GSDMD cleavage in sepsis liver injury","pmids":["32332915"],"confidence":"High","gaps":["Binding interface and nucleotide dependence of the PGC-1α interaction not mapped"]},{"year":2020,"claim":"Extended HSPA12A function to ubiquitin-proteasome control of a substrate by showing it recruits an E3 ligase to degrade a glycolytic transporter.","evidence":"MS interactome, Co-IP for HSPA12A–HRD1, cycloheximide/MG132 stability assays, and CD147 rescue in renal cell carcinoma","pmids":["32754264"],"confidence":"High","gaps":["Whether HSPA12A is a co-factor versus adaptor for HRD1 unclear","Direct CD147 contact not demonstrated"]},{"year":2021,"claim":"Linked HSPA12A to endothelial protective kinase signaling, showing it preserves barrier integrity through ERK/Akt activation.","evidence":"HUVEC overexpression, Hspa12a-/- LPS-ALI mice, and ERK/Akt inhibitor rescue with permeability and VE-cadherin/VEGF readouts","pmids":["34343936"],"confidence":"Medium","gaps":["How HSPA12A activates ERK/Akt is unknown","No direct upstream effector identified"]},{"year":2021,"claim":"Connected HSPA12A to PGC-1α-dependent mitochondrial integrity in skeletal muscle, positioning it upstream of mitochondrial protection.","evidence":"C2C12 overexpression, SR-18292 PGC-1α inhibitor rescue, mitochondrial morphology/ATP assays, and bupivacaine in vivo model","pmids":["34793778"],"confidence":"Medium","gaps":["No direct HSPA12A–PGC1α binding shown in this study","Mechanism of PGC1α nuclear retention unaddressed"]},{"year":2022,"claim":"Showed HSPA12A drives angiogenesis through p38/ERK→AP-1 signaling and pro-angiogenic gene expression.","evidence":"Endothelial gain/loss-of-function, Hspa12a-/- MI mice, p38/ERK inhibitor rescue, nuclear fractionation, and tube-formation assays","pmids":["35783189"],"confidence":"Medium","gaps":["Direct molecular trigger of MAPK activation by HSPA12A unknown"]},{"year":2022,"claim":"Revealed post-transcriptional control of HSPA12A itself, with an exon-2-retaining isoform that stabilizes N-cadherin mRNA in colorectal cancer.","evidence":"CLIP for SRSF11 binding, mini-gene splicing reporter, RNA-seq, in vitro PAK5 kinase assay, and RNA stability assays","pmids":["36394206"],"confidence":"Medium","gaps":["Functional difference between isoforms at protein level not dissected","Single lab"]},{"year":2023,"claim":"Defined the glycolysis→lactate→protein lactylation axis as a core HSPA12A output, with hepatocyte HSPA12A limiting HMGB1 lactylation and macrophage recruitment.","evidence":"Hepatocyte-specific overexpression and Hspa12a-/- mice, HMGB1 lactylation Co-IP, HMGB1 knockdown rescue, and chemotaxis assays in liver I/R","pmids":["37441587"],"confidence":"High","gaps":["How HSPA12A lowers hepatocyte glycolysis molecularly not fully resolved"]},{"year":2023,"claim":"Established HSPA12A as a regulator of cerebral lactate homeostasis via GSK3β inhibition, linking its metabolic role to neurogenesis and behavior.","evidence":"Hspa12a-/- behavioral tests, BrdU neurogenesis, CSF lactate measurement, neuronal overexpression, and lactate rescue administration","pmids":["37580315"],"confidence":"Medium","gaps":["GSK3β inhibition mechanism less directly validated","Direct HSPA12A–GSK3β interaction not shown"]},{"year":2024,"claim":"Demonstrated a scaffolding function in protein stabilization by showing HSPA12A bridges p53 and USP10 to promote p53 deubiquitination and limit cardiac fibrosis.","evidence":"Co-IP of HSPA12A–p53 and HSPA12A–USP10, cycloheximide/MG132 stability assays, Hspa12a-/- MI mice, and fibrosis staining","pmids":["38219869"],"confidence":"High","gaps":["Stoichiometry and binding interfaces of the ternary complex unresolved"]},{"year":2024,"claim":"Connected HSPA12A to HIF1α-driven glycolysis and histone H3 lactylation supporting cardiomyocyte survival after reperfusion.","evidence":"Hspa12a-/- MI/R mice, cardiomyocyte gain/loss-of-function, glycolytic flux, H3 lactylation assay, and Smurf1-dependent HIF1α stability analysis","pmids":["38421727"],"confidence":"Medium","gaps":["Direct HSPA12A–Smurf1 interaction evidence limited","How HSPA12A modulates Smurf1 activity unknown"]},{"year":2024,"claim":"Showed HSPA12A both binds c-Myc to enhance its nuclear localization and amplifies c-Myc lactylation through HIF1α-dependent lactate, driving renal tubular proliferation.","evidence":"Co-IP for HSPA12A–c-Myc, c-Myc lactylation assay with inhibitor rescue, nuclear fractionation, and Hspa12a-/- KI/R model","pmids":["39277835"],"confidence":"Medium","gaps":["Relative contribution of direct binding versus lactylation to nuclear c-Myc unclear"]},{"year":2024,"claim":"Dissected the Smurf1→HIF1α→glycolysis pathway in renal tubular cells, distinguishing HIF1α protein stabilization from transcription.","evidence":"HK-2 gain/loss-of-function, YC-1 HIF1α inhibitor, cycloheximide stability assays, qPCR, and glycolysis inhibitors after hypoxia/reoxygenation","pmids":["39349238"],"confidence":"Medium","gaps":["In vitro only","Direct HSPA12A–Smurf1 binding not demonstrated"]},{"year":2024,"claim":"Identified an mTOR-autophagy axis through which HSPA12A promotes TLR4/NF-κB inflammation in septic cardiomyopathy, contrasting with its protective roles elsewhere.","evidence":"Hspa12a-/- CLP sepsis mice, cardiomyocyte overexpression, rapamycin rescue, LC3-II/p62 and NF-κB immunoblotting, and death staining","pmids":["39642573"],"confidence":"Medium","gaps":["How HSPA12A activates mTOR is unknown","Cell-type basis of protective-versus-deleterious outcomes unresolved"]},{"year":null,"claim":"It remains unknown whether HSPA12A possesses intrinsic chaperone/ATPase activity and how a single protein achieves context-dependent partner selectivity across trafficking, ubiquitin-pathway, and glycolytic functions.","evidence":"No structural or biochemical reconstitution of HSPA12A activity is present in the corpus","pmids":[],"confidence":"Low","gaps":["No structural model or domain-level dissection","Nucleotide-dependence shown only for SorLA binding","No unified rule for partner selection across cell types"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,10,11,15]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2,10]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8,11,15,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,1,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6]}],"complexes":[],"partners":["PGC1A","PKM2","HRD1","TP53","USP10","MYC","SORL1","SRSF11"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43301","full_name":"Heat shock 70 kDa protein 12A","aliases":["Heat shock protein family A member 12A"],"length_aa":675,"mass_kda":75.0,"function":"Adapter protein for SORL1, but not SORT1. Delays SORL1 internalization and affects SORL1 subcellular localization","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O43301/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HSPA12A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000165868","cell_line_id":"CID000044","localizations":[{"compartment":"membrane","grade":3},{"compartment":"cell_contact","grade":2},{"compartment":"cytoplasmic","grade":1},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"AKAP12","stoichiometry":4.0},{"gene":"PRKAR2A","stoichiometry":0.2},{"gene":"EPB41L3","stoichiometry":0.2},{"gene":"ITPR3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000044","total_profiled":1310},"omim":[{"mim_id":"610702","title":"HEAT-SHOCK 70-KD PROTEIN 12B; HSPA12B","url":"https://www.omim.org/entry/610702"},{"mim_id":"610701","title":"HEAT-SHOCK 70-KD PROTEIN 12A; HSPA12A","url":"https://www.omim.org/entry/610701"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":27.0}],"url":"https://www.proteinatlas.org/search/HSPA12A"},"hgnc":{"alias_symbol":["FLJ13874","KIAA0417"],"prev_symbol":[]},"alphafold":{"accession":"O43301","domains":[{"cath_id":"2.60.34.10","chopping":"25-42_536-670","consensus_level":"high","plddt":82.5319,"start":25,"end":670},{"cath_id":"3.30.420.40","chopping":"58-237","consensus_level":"medium","plddt":91.9746,"start":58,"end":237},{"cath_id":"3.30.420.40","chopping":"240-259_294-346_460-532","consensus_level":"medium","plddt":88.0929,"start":240,"end":532},{"cath_id":"-","chopping":"350-451","consensus_level":"medium","plddt":94.0945,"start":350,"end":451}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43301","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43301-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43301-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HSPA12A","jax_strain_url":"https://www.jax.org/strain/search?query=HSPA12A"},"sequence":{"accession":"O43301","fasta_url":"https://rest.uniprot.org/uniprotkb/O43301.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43301/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43301"}},"corpus_meta":[{"pmid":"25798051","id":"PMC_25798051","title":"Upregulation of heat shock proteins (HSPA12A, HSP90B1, HSPA4, HSPA5 and HSPA6) in tumour tissues is associated with poor outcomes from HBV-related early-stage hepatocellular carcinoma.","date":"2015","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25798051","citation_count":149,"is_preprint":false},{"pmid":"37441587","id":"PMC_37441587","title":"Hepatocyte HSPA12A inhibits macrophage chemotaxis and activation to attenuate liver ischemia/reperfusion injury via suppressing glycolysis-mediated HMGB1 lactylation and secretion of hepatocytes.","date":"2023","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/37441587","citation_count":126,"is_preprint":false},{"pmid":"32332915","id":"PMC_32332915","title":"HSPA12A attenuates lipopolysaccharide-induced liver injury through inhibiting caspase-11-mediated hepatocyte pyroptosis via PGC-1α-dependent acyloxyacyl hydrolase expression.","date":"2020","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/32332915","citation_count":87,"is_preprint":false},{"pmid":"30455376","id":"PMC_30455376","title":"HSPA12A Is a Novel Player in Nonalcoholic Steatohepatitis via Promoting Nuclear PKM2-Mediated M1 Macrophage Polarization.","date":"2018","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/30455376","citation_count":66,"is_preprint":false},{"pmid":"38421727","id":"PMC_38421727","title":"HSPA12A maintains aerobic glycolytic homeostasis and Histone3 lactylation in cardiomyocytes to attenuate myocardial ischemia/reperfusion injury.","date":"2024","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/38421727","citation_count":49,"is_preprint":false},{"pmid":"30742088","id":"PMC_30742088","title":"HSPA12A is required for adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPARγ.","date":"2019","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/30742088","citation_count":38,"is_preprint":false},{"pmid":"32754264","id":"PMC_32754264","title":"HSPA12A unstabilizes CD147 to inhibit lactate export and migration in human renal cell carcinoma.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/32754264","citation_count":30,"is_preprint":false},{"pmid":"23643947","id":"PMC_23643947","title":"The response profiles of HSPA12A and TCTP from Mytilus galloprovincialis to pathogen and cadmium challenge.","date":"2013","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23643947","citation_count":24,"is_preprint":false},{"pmid":"38219869","id":"PMC_38219869","title":"HSPA12A acts as a scaffolding protein to inhibit cardiac fibroblast activation and cardiac fibrosis.","date":"2024","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/38219869","citation_count":21,"is_preprint":false},{"pmid":"39277835","id":"PMC_39277835","title":"HSPA12A promotes c-Myc lactylation-mediated proliferation of tubular epithelial cells to facilitate renal functional recovery from kidney ischemia/reperfusion injury.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/39277835","citation_count":19,"is_preprint":false},{"pmid":"36394206","id":"PMC_36394206","title":"Alternative splicing of HSPA12A pre-RNA by SRSF11 contributes to metastasis potential of colorectal cancer.","date":"2022","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36394206","citation_count":19,"is_preprint":false},{"pmid":"26302849","id":"PMC_26302849","title":"Polymorphisms of PRLHR and HSPA12A and risk of gastric and colorectal cancer in the Chinese Han population.","date":"2015","source":"BMC gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/26302849","citation_count":15,"is_preprint":false},{"pmid":"34343936","id":"PMC_34343936","title":"HSPA12A improves endothelial integrity to attenuate lung injury during endotoxemia through activating ERKs and Akt-dependent signaling.","date":"2021","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34343936","citation_count":14,"is_preprint":false},{"pmid":"37580315","id":"PMC_37580315","title":"HSPA12A controls cerebral lactate homeostasis to maintain hippocampal neurogenesis and mood stabilization.","date":"2023","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/37580315","citation_count":12,"is_preprint":false},{"pmid":"30679749","id":"PMC_30679749","title":"HSPA12A targets the cytoplasmic domain and affects the trafficking of the Amyloid Precursor Protein receptor SorLA.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30679749","citation_count":11,"is_preprint":false},{"pmid":"35783189","id":"PMC_35783189","title":"HSPA12A Stimulates p38/ERK-AP-1 Signaling to Promote Angiogenesis and Is Required for Functional Recovery Postmyocardial Infarction.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/35783189","citation_count":10,"is_preprint":false},{"pmid":"39642573","id":"PMC_39642573","title":"Downregulation of HSPA12A protects heart against sepsis through suppressing mTOR-mediated inflammatory response in cardiomyocytes.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39642573","citation_count":7,"is_preprint":false},{"pmid":"39349238","id":"PMC_39349238","title":"HSPA12A stimulates \"Smurf1-Hif1α-aerobic glycolysis\" axis to promote proliferation of renal tubular epithelial cells after hypoxia/reoxygenation injury.","date":"2024","source":"Cell stress & chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/39349238","citation_count":2,"is_preprint":false},{"pmid":"37245169","id":"PMC_37245169","title":"HSPA12A was identified as a key driver in colorectal cancer GWAS loci 10q26.12 and modulated by an enhancer-promoter interaction.","date":"2023","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/37245169","citation_count":2,"is_preprint":false},{"pmid":"34793778","id":"PMC_34793778","title":"Downregulation of HSPA12A underlies myotoxicity of local anesthetic agent bupivacaine through inhibiting PGC1α-mediated mitochondrial integrity.","date":"2021","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34793778","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14463,"output_tokens":5042,"usd":0.059509,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13503,"output_tokens":5179,"usd":0.098495,"stage2_stop_reason":"end_turn"},"total_usd":0.158004,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"HSPA12A selectively binds to the cytoplasmic domain of SorLA (but not Sortilin) in an ADP/ATP-dependent manner, mediated by specific acidic residues in SorLA's cytosolic domain, and this interaction affects both endocytic speed and subcellular localization of SorLA. This is the first described substrate/binding partner of HSPA12A.\",\n      \"method\": \"Co-immunoprecipitation/pulldown, ADP/ATP-dependent binding assay, site-directed mutagenesis of SorLA acidic residues, subcellular localization assay, endocytosis assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assay with mechanistic mutagenesis, single lab with multiple orthogonal methods but no independent replication\",\n      \"pmids\": [\"30679749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HSPA12A directly interacts with PGC-1α in hepatocytes and increases its nuclear translocation, thereby inducing AOAH (acyloxyacyl hydrolase) expression, which inactivates cytosolic LPS and inhibits Caspase-11-mediated gasdermin D cleavage (pyroptosis) during sepsis-induced liver injury.\",\n      \"method\": \"Immunoprecipitation (direct protein interaction), loss- and gain-of-function studies (Hspa12a-/- mice and overexpression), immunoblotting for Caspase-11 and GSDMD cleavage, AOAH overexpression rescue experiment\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing direct interaction, genetic KO mouse model, rescue experiments with AOAH overexpression, multiple orthogonal methods in one study\",\n      \"pmids\": [\"32332915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HSPA12A interacts with the M2 isoform of pyruvate kinase (PKM2) in macrophages and promotes its nuclear translocation, thereby driving M1 macrophage polarization and secretion of pro-inflammatory cytokines, which in turn cause hepatocyte steatosis via paracrine effects in NASH.\",\n      \"method\": \"Immunoprecipitation (HSPA12A–PKM2 interaction), loss- and gain-of-function in macrophages, nuclear fractionation, Hspa12a-/- mice on high-fat diet, paracrine co-culture assays\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP establishing direct interaction, genetic KO mouse model, multiple functional readouts and rescue experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30455376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HSPA12A is required for adipocyte differentiation through a positive feedback loop with PPARγ: PPARγ directly binds the PPAR response element in the Hspa12a promoter (confirmed by ChIP), activating HSPA12A expression, while HSPA12A in turn promotes PPARγ expression and adipogenic gene transcription during differentiation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for PPARγ binding to Hspa12a promoter, Hspa12a-/- mouse model (high-fat diet), PPARγ inhibitor (GW9662) rescue, loss- and gain-of-function in primary adipocyte precursors\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP establishes direct transcriptional regulation, KO mouse phenotype, pharmacological rescue, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"30742088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HSPA12A in renal cell carcinoma (RCC) cells interacts with HRD1 ubiquitin E3 ligase and promotes ubiquitin-proteasome degradation of CD147, thereby reducing lactate export and glycolysis, and suppressing RCC cell migration. CD147 overexpression abolishes HSPA12A's inhibitory effects on lactate export and migration.\",\n      \"method\": \"Mass spectrometry (interactome), immunoprecipitation (HSPA12A–HRD1 interaction), cycloheximide chase and MG132 proteasome inhibitor assays (protein stability), CD147 overexpression rescue, Transwell migration and wound healing assays, Seahorse glycolysis assay\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-identified interaction confirmed by Co-IP, proteasome degradation mechanism validated with multiple pharmacological tools, rescue experiment, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"32754264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HSPA12A overexpression in endothelial cells protects against LPS-induced endothelial hyperpermeability and death by activating ERKs and Akt phosphorylation; pharmacological inhibition of either ERKs or Akt abolished HSPA12A's protective effects. HSPA12A also upregulated VE-cadherin and downregulated VEGF expression.\",\n      \"method\": \"HSPA12A overexpression in HUVECs, Hspa12a-/- mouse model (LPS-induced ALI), ERK/Akt inhibitor treatment, immunoblotting for phosphorylation, permeability assay, cell death assay\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model plus in vitro gain-of-function with pharmacological inhibitor rescue, single lab\",\n      \"pmids\": [\"34343936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HSPA12A promotes angiogenesis in endothelial cells by activating p38 and ERK phosphorylation, leading to increased AP-1 phosphorylation and nuclear localization, which drives expression of VEGF, VEGFR2, and Ang-1. Inhibition of p38 or ERKs abolished HSPA12A-promoted AP-1 activation and angiogenic characteristics.\",\n      \"method\": \"HSPA12A overexpression/deficiency in endothelial cells, Hspa12a-/- mouse MI model, p38/ERK inhibitor pharmacological rescue, immunoblotting for phosphorylation, nuclear fractionation, tube formation/migration/proliferation assays, echocardiography\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with defined MI phenotype plus in vitro pathway dissection with pharmacological inhibitors, single lab\",\n      \"pmids\": [\"35783189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRSF11 directly binds a motif in exon 2 of HSPA12A pre-mRNA (confirmed by CLIP and mini-gene assay) and promotes exon 2 skipping; the HSPA12A transcript retaining exon 2 increases N-cadherin expression by enhancing RNA stability, thereby promoting colorectal cancer metastasis. PAK5 phosphorylates SRSF11 at serine 287 to protect it from ubiquitination, maintaining SRSF11-mediated HSPA12A splicing regulation.\",\n      \"method\": \"UV crosslinking and immunoprecipitation (CLIP), mini-gene reporter assay, RNA-seq, in vitro kinase assay (PAK5 phosphorylates SRSF11), Co-IP, Phospho-tag SDS-PAGE, RNA stability assay\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLIP establishes direct RNA-protein interaction, mini-gene validates splicing, in vitro kinase assay validates phosphorylation; single lab\",\n      \"pmids\": [\"36394206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Hepatocyte HSPA12A overexpression reduces glycolysis-generated lactate, thereby decreasing HMGB1 lactylation and secretion from hepatocytes during liver ischemia/reperfusion (LI/R); HMGB1 knockdown reversed the deleterious effects of HSPA12A knockout on macrophage chemotaxis and inflammatory activation, placing HSPA12A upstream of glycolysis → lactate → HMGB1 lactylation → macrophage recruitment in LI/R injury.\",\n      \"method\": \"Hepatocyte-specific HSPA12A overexpression (in vivo), Hspa12a-/- mice, HMGB1 knockdown rescue, immunoprecipitation for HMGB1 lactylation, Transwell chemotaxis assay, exosome HMGB1 quantification, ALT/AST assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — hepatocyte-specific overexpression and KO mouse models, HMGB1 lactylation confirmed by Co-IP, genetic rescue with HMGB1 knockdown, multiple orthogonal methods in single study\",\n      \"pmids\": [\"37441587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HSPA12A in hippocampal neurons inhibits GSK3β to sustain glycolytic enzyme expression and lactate production; Hspa12a-/- mice show decreased CSF lactate, impaired adult hippocampal neurogenesis, and mood instability behaviors, all of which are rescued by lactate administration, establishing HSPA12A as a regulator of cerebral lactate homeostasis via GSK3β inhibition.\",\n      \"method\": \"Hspa12a-/- mouse behavioral tests (open field, forced swimming, elevated plus maze, sucrose preference), BrdU neurogenesis labeling, CSF lactate measurement, HSPA12A overexpression in primary hippocampal neurons (glycolysis readout), lactate rescue administration\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with multiple behavioral readouts, lactate rescue establishes pathway position, single lab; GSK3β inhibition mechanism is less directly validated\",\n      \"pmids\": [\"37580315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HSPA12A acts as a scaffolding protein in cardiac fibroblasts by binding both p53 and USP10 (ubiquitin-specific protease 10) simultaneously, thereby promoting USP10-mediated deubiquitination and stabilization of p53 protein, which in turn inhibits glycolysis and prevents cardiac fibroblast activation into myofibroblasts; Hspa12a-/- mice showed exacerbated cardiac fibrosis post-MI.\",\n      \"method\": \"Immunoprecipitation-immunoblotting (HSPA12A–p53 and HSPA12A–USP10 interactions), cycloheximide and MG132 stability assays, Hspa12a-/- mouse MI model, Masson/picrosirius staining for fibrosis, echocardiography, primary cardiac fibroblast loss/gain-of-function\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP establishes ternary scaffolding complex, protein stability validated by multiple pharmacological tools, KO mouse phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"38219869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In cardiomyocytes, HSPA12A maintains aerobic glycolysis during reperfusion by increasing Smurf1-mediated HIF1α protein stability, which upregulates glycolytic gene expression and sustains H3 (Histone 3) lactylation as an epigenetic mechanism supporting cardiomyocyte survival; Hspa12a-/- mice showed exacerbated aerobic glycolysis decrease and worse MI/R injury.\",\n      \"method\": \"Hspa12a-/- mouse MI/R model, gain- and loss-of-function in cardiomyocytes, glycolytic flux measurement, H3 lactylation assay (epigenetic readout), HIF1α protein stability assay, Smurf1-dependent mechanism analysis, echocardiography\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with defined cardiac phenotype, multiple mechanistic layers assessed, single lab; Smurf1–HIF1α mechanism described but direct HSPA12A–Smurf1 interaction evidence limited to abstract summary\",\n      \"pmids\": [\"38421727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HSPA12A directly interacts with c-Myc in renal tubular epithelial cells and enhances its nuclear localization; HSPA12A also promotes glycolysis-derived lactate generation in a HIF1α-dependent manner, increasing c-Myc lactylation, which further enhances c-Myc nuclear localization and transcription of proliferation-related genes to support TEC proliferation after KI/R; inhibiting c-Myc lactylation abolished HSPA12A-induced proliferation.\",\n      \"method\": \"Co-immunoprecipitation (HSPA12A–c-Myc direct interaction), c-Myc lactylation assay, pharmacological inhibition of c-Myc lactylation, nuclear fractionation, gain-of-function HSPA12A overexpression, HIF1α-dependent mechanism analysis, Hspa12a-/- mouse KI/R model\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes direct HSPA12A–c-Myc interaction, lactylation inhibitor rescue validates mechanism, KO mouse model; single lab\",\n      \"pmids\": [\"39277835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In cardiomyocytes during sepsis, HSPA12A overexpression activates mTOR and inhibits autophagy, thereby enhancing TLR4/MyD88/NF-κB-mediated inflammation; conversely, HSPA12A knockout attenuated sepsis-induced cardiomyocyte death and cardiac dysfunction. Rapamycin (mTOR inhibitor) abolished the HSPA12A-induced autophagy inhibition and inflammation, placing HSPA12A upstream of mTOR-autophagy in the septic cardiomyopathy pathway.\",\n      \"method\": \"Hspa12a-/- mouse CLP sepsis model, HSPA12A overexpression in primary cardiomyocytes, rapamycin pharmacological rescue, LC3-II/p62 autophagy markers, NF-κB pathway immunoblotting, TUNEL/PI death staining, echocardiography\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with defined cardiac sepsis phenotype, pharmacological mTOR inhibitor rescue validates pathway, single lab\",\n      \"pmids\": [\"39642573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HSPA12A downregulation during bupivacaine-induced myotoxicity underlies mitochondrial damage in skeletal muscle; HSPA12A overexpression attenuated bupivacaine-induced cell death, restored glucose consumption and ATP production, reduced mitochondrial fragmentation, and maintained PGC1α expression and nuclear localization. Pharmacological inhibition of PGC1α (SR-18292) abolished HSPA12A-mediated protection, placing HSPA12A upstream of PGC1α-mediated mitochondrial integrity.\",\n      \"method\": \"HSPA12A overexpression in C2C12 myoblasts, PGC1α inhibitor (SR-18292) rescue, mitochondrial content and morphology assay, ATP production assay, PGC1α nuclear fractionation, Bupivacaine in vivo mouse model\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function plus pharmacological rescue establishes pathway, in vitro and in vivo data, single lab; no direct HSPA12A–PGC1α binding shown in this paper (interaction established in PMID:32332915)\",\n      \"pmids\": [\"34793778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HSPA12A promotes HIF1α protein stability through a Smurf1-dependent mechanism in renal tubular epithelial cells (HK-2) after hypoxia/reoxygenation, independently of HIF1α transcription; HIF1α pharmacological inhibition (YC-1) abolished HSPA12A-promoted glycolytic flux and cell proliferation, confirming HSPA12A acts through Smurf1→HIF1α→glycolysis to support TEC proliferation.\",\n      \"method\": \"HSPA12A gain- and loss-of-function in HK-2 cells, HIF1α inhibitor (YC-1), cycloheximide protein stability assay, qPCR (HIF1α transcription vs. protein), glycolysis inhibitors (2-DG, oxamate), proliferation assay\",\n      \"journal\": \"Cell stress & chaperones\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological inhibitors dissect pathway, protein stability vs. transcription distinguished; single lab, in vitro only\",\n      \"pmids\": [\"39349238\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HSPA12A is an atypical HSP70-family member that functions primarily as a scaffolding/chaperone-like protein rather than a classical chaperone: it directly binds partners including PGC-1α, PKM2, p53/USP10, HRD1, c-Myc, and the SorLA cytoplasmic domain to modulate their nuclear translocation, ubiquitin-proteasome stability, or subcellular trafficking; in parallel, it sustains aerobic glycolysis (via Smurf1-HIF1α stabilization and GSK3β inhibition) to regulate lactate production, protein lactylation (HMGB1, c-Myc, H3), and downstream transcriptional programs, thereby controlling diverse cell-type-specific processes including hepatocyte pyroptosis, macrophage M1 polarization, adipocyte differentiation, cardiac fibroblast activation, endothelial barrier integrity, angiogenesis, and renal tubular cell proliferation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HSPA12A is an atypical HSP70-family protein that acts as a scaffold and trafficking/stability modulator for diverse partner proteins and, in parallel, sustains aerobic glycolysis to drive lactate-dependent signaling and epigenetic programs across multiple cell types [#1, #8]. As a binding protein, it engages partners in an ADP/ATP-dependent manner—first shown for the SorLA cytoplasmic domain, where binding controls SorLA endocytic speed and subcellular localization [#0]—and it directs the nuclear translocation of transcriptional and metabolic regulators including PGC-1\\u03b1 in hepatocytes and skeletal muscle [#1, #14], PKM2 in macrophages [#2], and c-Myc in renal tubular cells [#12]. HSPA12A also governs protein stability through ubiquitin-pathway components: it recruits the HRD1 E3 ligase to drive proteasomal degradation of CD147 [#4], and it forms a ternary complex with p53 and USP10 that promotes USP10-mediated deubiquitination and stabilization of p53 [#10]. A recurrent theme is metabolic control: HSPA12A increases Smurf1-dependent HIF1\\u03b1 protein stability and inhibits GSK3\\u03b2 to sustain glycolytic gene expression and lactate output [#11, #15, #9], and the resulting lactate fuels lactylation of HMGB1, c-Myc, and histone H3 to regulate downstream inflammatory, proliferative, and survival programs [#8, #12, #11]. Through these activities HSPA12A controls cell-type-specific outcomes including hepatocyte pyroptosis [#1], macrophage M1 polarization [#2], adipocyte differentiation via a PPAR\\u03b3 feedback loop [#3], cardiac fibroblast activation [#10], endothelial barrier integrity and angiogenesis [#5, #6], and renal tubular cell proliferation [#12, #15]. Its own expression is regulated transcriptionally by PPAR\\u03b3 [#3] and post-transcriptionally by SRSF11-mediated exon 2 splicing [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established the first functional link between HSPA12A and metabolic-transcriptional reprogramming by showing it controls nuclear translocation of a partner protein.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, and Hspa12a-/- mice in macrophages identifying HSPA12A\\u2013PKM2 interaction driving M1 polarization in NASH\",\n      \"pmids\": [\"30455376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which HSPA12A enhances PKM2 nuclear import not defined\", \"Direct binding interface unmapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the first direct binding partner of HSPA12A and showed binding is nucleotide-dependent, framing it as an HSP70-like scaffold acting on cargo trafficking.\",\n      \"evidence\": \"Reciprocal Co-IP/pulldown with ADP/ATP-dependent binding assays and SorLA acidic-residue mutagenesis, plus endocytosis assays\",\n      \"pmids\": [\"30679749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No independent replication\", \"Selectivity for SorLA over Sortilin mechanistically unexplained\", \"No structural model of the interaction\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed HSPA12A within a transcriptional feedback circuit by establishing both that PPAR\\u03b3 directly drives its expression and that it is required for adipogenesis.\",\n      \"evidence\": \"ChIP for PPAR\\u03b3 binding to the Hspa12a promoter, Hspa12a-/- mice, and GW9662 pharmacological rescue in primary adipocyte precursors\",\n      \"pmids\": [\"30742088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which HSPA12A promotes PPAR\\u03b3 expression unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated HSPA12A directly binds PGC-1\\u03b1 and routes it to the nucleus to suppress hepatocyte pyroptosis, generalizing the nuclear-translocation scaffold model to a protective metabolic regulator.\",\n      \"evidence\": \"Reciprocal Co-IP, Hspa12a-/- mice, and AOAH overexpression rescue measuring Caspase-11/GSDMD cleavage in sepsis liver injury\",\n      \"pmids\": [\"32332915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface and nucleotide dependence of the PGC-1\\u03b1 interaction not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended HSPA12A function to ubiquitin-proteasome control of a substrate by showing it recruits an E3 ligase to degrade a glycolytic transporter.\",\n      \"evidence\": \"MS interactome, Co-IP for HSPA12A\\u2013HRD1, cycloheximide/MG132 stability assays, and CD147 rescue in renal cell carcinoma\",\n      \"pmids\": [\"32754264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HSPA12A is a co-factor versus adaptor for HRD1 unclear\", \"Direct CD147 contact not demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked HSPA12A to endothelial protective kinase signaling, showing it preserves barrier integrity through ERK/Akt activation.\",\n      \"evidence\": \"HUVEC overexpression, Hspa12a-/- LPS-ALI mice, and ERK/Akt inhibitor rescue with permeability and VE-cadherin/VEGF readouts\",\n      \"pmids\": [\"34343936\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How HSPA12A activates ERK/Akt is unknown\", \"No direct upstream effector identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected HSPA12A to PGC-1\\u03b1-dependent mitochondrial integrity in skeletal muscle, positioning it upstream of mitochondrial protection.\",\n      \"evidence\": \"C2C12 overexpression, SR-18292 PGC-1\\u03b1 inhibitor rescue, mitochondrial morphology/ATP assays, and bupivacaine in vivo model\",\n      \"pmids\": [\"34793778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct HSPA12A\\u2013PGC1\\u03b1 binding shown in this study\", \"Mechanism of PGC1\\u03b1 nuclear retention unaddressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed HSPA12A drives angiogenesis through p38/ERK\\u2192AP-1 signaling and pro-angiogenic gene expression.\",\n      \"evidence\": \"Endothelial gain/loss-of-function, Hspa12a-/- MI mice, p38/ERK inhibitor rescue, nuclear fractionation, and tube-formation assays\",\n      \"pmids\": [\"35783189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular trigger of MAPK activation by HSPA12A unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed post-transcriptional control of HSPA12A itself, with an exon-2-retaining isoform that stabilizes N-cadherin mRNA in colorectal cancer.\",\n      \"evidence\": \"CLIP for SRSF11 binding, mini-gene splicing reporter, RNA-seq, in vitro PAK5 kinase assay, and RNA stability assays\",\n      \"pmids\": [\"36394206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional difference between isoforms at protein level not dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the glycolysis\\u2192lactate\\u2192protein lactylation axis as a core HSPA12A output, with hepatocyte HSPA12A limiting HMGB1 lactylation and macrophage recruitment.\",\n      \"evidence\": \"Hepatocyte-specific overexpression and Hspa12a-/- mice, HMGB1 lactylation Co-IP, HMGB1 knockdown rescue, and chemotaxis assays in liver I/R\",\n      \"pmids\": [\"37441587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HSPA12A lowers hepatocyte glycolysis molecularly not fully resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established HSPA12A as a regulator of cerebral lactate homeostasis via GSK3\\u03b2 inhibition, linking its metabolic role to neurogenesis and behavior.\",\n      \"evidence\": \"Hspa12a-/- behavioral tests, BrdU neurogenesis, CSF lactate measurement, neuronal overexpression, and lactate rescue administration\",\n      \"pmids\": [\"37580315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GSK3\\u03b2 inhibition mechanism less directly validated\", \"Direct HSPA12A\\u2013GSK3\\u03b2 interaction not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a scaffolding function in protein stabilization by showing HSPA12A bridges p53 and USP10 to promote p53 deubiquitination and limit cardiac fibrosis.\",\n      \"evidence\": \"Co-IP of HSPA12A\\u2013p53 and HSPA12A\\u2013USP10, cycloheximide/MG132 stability assays, Hspa12a-/- MI mice, and fibrosis staining\",\n      \"pmids\": [\"38219869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and binding interfaces of the ternary complex unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected HSPA12A to HIF1\\u03b1-driven glycolysis and histone H3 lactylation supporting cardiomyocyte survival after reperfusion.\",\n      \"evidence\": \"Hspa12a-/- MI/R mice, cardiomyocyte gain/loss-of-function, glycolytic flux, H3 lactylation assay, and Smurf1-dependent HIF1\\u03b1 stability analysis\",\n      \"pmids\": [\"38421727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HSPA12A\\u2013Smurf1 interaction evidence limited\", \"How HSPA12A modulates Smurf1 activity unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed HSPA12A both binds c-Myc to enhance its nuclear localization and amplifies c-Myc lactylation through HIF1\\u03b1-dependent lactate, driving renal tubular proliferation.\",\n      \"evidence\": \"Co-IP for HSPA12A\\u2013c-Myc, c-Myc lactylation assay with inhibitor rescue, nuclear fractionation, and Hspa12a-/- KI/R model\",\n      \"pmids\": [\"39277835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of direct binding versus lactylation to nuclear c-Myc unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Dissected the Smurf1\\u2192HIF1\\u03b1\\u2192glycolysis pathway in renal tubular cells, distinguishing HIF1\\u03b1 protein stabilization from transcription.\",\n      \"evidence\": \"HK-2 gain/loss-of-function, YC-1 HIF1\\u03b1 inhibitor, cycloheximide stability assays, qPCR, and glycolysis inhibitors after hypoxia/reoxygenation\",\n      \"pmids\": [\"39349238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro only\", \"Direct HSPA12A\\u2013Smurf1 binding not demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified an mTOR-autophagy axis through which HSPA12A promotes TLR4/NF-\\u03baB inflammation in septic cardiomyopathy, contrasting with its protective roles elsewhere.\",\n      \"evidence\": \"Hspa12a-/- CLP sepsis mice, cardiomyocyte overexpression, rapamycin rescue, LC3-II/p62 and NF-\\u03baB immunoblotting, and death staining\",\n      \"pmids\": [\"39642573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How HSPA12A activates mTOR is unknown\", \"Cell-type basis of protective-versus-deleterious outcomes unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether HSPA12A possesses intrinsic chaperone/ATPase activity and how a single protein achieves context-dependent partner selectivity across trafficking, ubiquitin-pathway, and glycolytic functions.\",\n      \"evidence\": \"No structural or biochemical reconstitution of HSPA12A activity is present in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model or domain-level dissection\", \"Nucleotide-dependence shown only for SorLA binding\", \"No unified rule for partner selection across cell types\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 10, 11, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8, 11, 15, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 1, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PGC1A\", \"PKM2\", \"HRD1\", \"TP53\", \"USP10\", \"MYC\", \"SORL1\", \"SRSF11\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}