{"gene":"HSPA12A","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2019,"finding":"HSPA12A selectively binds to the cytosolic domain of SorLA (an amyloid precursor protein receptor) in an ADP/ATP-dependent manner via specific acidic residues in SorLA's cytosolic domain, acting as an adaptor protein that affects both endocytic speed and subcellular localization of SorLA.","method":"Co-immunoprecipitation, pulldown, ADP/ATP-dependent binding assays, trafficking assays in cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal interaction with functional consequence (trafficking), single lab with multiple orthogonal methods","pmids":["30679749"],"is_preprint":false},{"year":2018,"finding":"In macrophages, HSPA12A directly interacts with PKM2 (M2 isoform of pyruvate kinase) and promotes its nuclear translocation, thereby driving M1 macrophage polarization and secretion of proinflammatory cytokines, which paracrinally induces hepatocyte steatosis in NASH.","method":"Co-immunoprecipitation, loss- and gain-of-function studies, nuclear fractionation, high-fat diet mouse model with Hspa12a knockout","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus KO mouse model with defined cellular phenotype and multiple orthogonal methods","pmids":["30455376"],"is_preprint":false},{"year":2020,"finding":"HSPA12A directly interacts with PGC-1α and promotes its nuclear translocation in hepatocytes, thereby inducing AOAH expression which inactivates cytosolic LPS and suppresses Caspase-11-mediated hepatocyte pyroptosis (GSDMD cleavage).","method":"Co-immunoprecipitation, loss- and gain-of-function in primary hepatocytes, Hspa12a-/- mice, nuclear fractionation, AOAH overexpression rescue experiments","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — direct interaction identified by Co-IP with functional rescue, KO mouse model, multiple orthogonal approaches","pmids":["32332915"],"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 to drive 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-/- mice on HFD, PPARγ inhibitor (GW9662) rescue, gain/loss-of-function in primary adipocytes","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP assay for direct promoter binding plus KO mouse model and pharmacological rescue","pmids":["30742088"],"is_preprint":false},{"year":2020,"finding":"HSPA12A interacts with HRD1 ubiquitin E3 ligase in renal cell carcinoma (RCC) cells, promoting CD147 ubiquitination and proteasomal degradation, thereby reducing lactate export and glycolysis to suppress RCC cell migration.","method":"Mass spectrometry, co-immunoprecipitation, immunoblotting, cycloheximide/MG132 protein stability assays, CD147 overexpression rescue, wound healing and Transwell migration assays","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — MS-identified interaction confirmed by Co-IP, mechanistic rescue with CD147 overexpression, multiple orthogonal methods in single lab","pmids":["32754264"],"is_preprint":false},{"year":2021,"finding":"HSPA12A overexpression in endothelial cells increases phosphorylation of ERKs and Akt, maintaining VE-cadherin expression and reducing VEGF expression, thereby preserving endothelial barrier integrity and protecting against LPS-induced acute lung injury; pharmacological inhibition of either ERKs or Akt abolishes these protective effects.","method":"HSPA12A KO mice (in vivo ALI model), HSPA12A overexpression in HUVECs, phosphorylation assays, ERK/Akt inhibitors as epistasis, permeability assays","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse phenotype plus pathway placement via pharmacological inhibitor epistasis, single lab","pmids":["34343936"],"is_preprint":false},{"year":2022,"finding":"HSPA12A promotes angiogenesis in endothelial cells by activating p38 and ERK phosphorylation, which drives AP-1 phosphorylation and nuclear localization, increasing expression of VEGF, VEGFR2, and Ang-1; inhibition of p38 or ERK abolished HSPA12A-promoted angiogenesis.","method":"HSPA12A KO mice post-MI, HSPA12A overexpression in endothelial cells, phosphorylation assays, pharmacological inhibition of p38/ERK, tube formation/migration/proliferation assays","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse model with defined phenotype plus pathway placed by pharmacological epistasis, single lab","pmids":["35783189"],"is_preprint":false},{"year":2022,"finding":"SRSF11 regulates alternative splicing of HSPA12A pre-mRNA by directly binding a motif in exon 2 (shown by UV-CLIP and minigene assay); the HSPA12A transcript with exon 2 retention promotes RNA stability and increases N-cadherin expression, facilitating colorectal cancer metastasis. PAK5 phosphorylates SRSF11 at serine 287 to protect it from ubiquitination degradation, placing HSPA12A downstream in a PAK5/SRSF11/HSPA12A axis.","method":"UV crosslinking and immunoprecipitation (CLIP), minigene reporter assay, Co-IP, Phospho-tag SDS-PAGE, in vitro kinase assay, RNA-seq","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical methods including in vitro kinase assay, CLIP, and minigene validation in single rigorous study","pmids":["36394206"],"is_preprint":false},{"year":2023,"finding":"HSPA12A overexpression suppresses glycolysis-generated lactate in hepatocytes, thereby reducing HMGB1 lactylation and its secretion in exosomes, which inhibits macrophage chemotaxis and inflammatory activation to protect against liver ischemia/reperfusion injury; HSPA12A knockout had opposite effects reversed by HMGB1 knockdown.","method":"Hepatocyte-specific HSPA12A overexpression, Hspa12a KO mice, Transwell chemotaxis assays, immunoprecipitation for lactylation, exosome HMGB1 measurement, HMGB1 knockdown rescue","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — hepatocyte-specific KO and OE in vivo and in vitro with molecular rescue (HMGB1 KD), multiple orthogonal methods","pmids":["37441587"],"is_preprint":false},{"year":2023,"finding":"HSPA12A maintains cerebral lactate homeostasis by inhibiting GSK3β in hippocampal neurons to sustain glycolytic enzyme expression and lactate production; Hspa12a-/- mice showed mood instability and impaired adult hippocampal neurogenesis that were rescued by lactate administration.","method":"Hspa12a-/- mouse behavioral tests, CSF lactate measurement, BrdU labeling for neurogenesis, HSPA12A OE in primary hippocampal neurons, lactate rescue experiments","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse model with defined cellular phenotype and rescue by lactate, pathway placement via GSK3β, single lab","pmids":["37580315"],"is_preprint":false},{"year":2024,"finding":"HSPA12A acts as a scaffolding protein binding both p53 and USP10 (ubiquitin specific protease 10) in cardiac fibroblasts, promoting USP10-mediated deubiquitination and stabilization of p53 protein, which then suppresses glycolysis and inhibits cardiac fibroblast activation and cardiac fibrosis.","method":"Co-immunoprecipitation-immunoblotting for HSPA12A-p53-USP10 ternary complex, cycloheximide/MG132 protein stability assays, Hspa12a KO mice post-MI, CF activation assays, Masson's trichrome staining","journal":"Journal of advanced research","confidence":"High","confidence_rationale":"Tier 2 — ternary complex identified by Co-IP with functional consequence shown in KO mouse, protein stability mechanistically explained, multiple orthogonal methods","pmids":["38219869"],"is_preprint":false},{"year":2024,"finding":"HSPA12A maintains aerobic glycolysis in cardiomyocytes during reperfusion by increasing Smurf1-mediated Hif1α protein stability, thereby upregulating glycolytic gene expression and sustaining Histone H3 lactylation; HSPA12A KO exacerbated MI/R-induced cardiomyocyte death and cardiac dysfunction.","method":"Hspa12a KO mice, gain/loss-of-function in cardiomyocytes, H3 lactylation assays, Hif1α protein stability assays (cycloheximide), Smurf1-dependent Hif1α stabilization, echocardiography","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — KO mouse model with defined cardiac phenotype, molecular pathway placed by Smurf1-Hif1α axis, multiple orthogonal methods","pmids":["38421727"],"is_preprint":false},{"year":2024,"finding":"HSPA12A directly interacts with c-Myc in renal tubular epithelial cells, enhancing c-Myc nuclear localization and lactylation (via Hif1α-dependent glycolysis-derived lactate), which drives proliferation-related gene expression and TEC proliferation to support renal recovery from ischemia/reperfusion injury.","method":"Co-immunoprecipitation for HSPA12A-c-Myc interaction, nuclear fractionation, c-Myc lactylation assays, Hif1α-dependent glycolysis experiments, Hspa12a KO mice post-KI/R, gain/loss-of-function in TEC","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 2 — direct interaction by Co-IP with nuclear localization consequence, KO mouse model, lactylation mechanistically linked, multiple orthogonal methods","pmids":["39277835"],"is_preprint":false},{"year":2024,"finding":"HSPA12A promotes Smurf1-dependent Hif1α protein stability (not transcription) to increase aerobic glycolytic flux and drive TEC proliferation after hypoxia/reoxygenation; glycolysis inhibition or Hif1α pharmacological inhibition (YC-1) abolished HSPA12A-promoted proliferation.","method":"Loss/gain-of-function in HK-2 cells, Hif1α protein stability assays, qPCR for transcription vs. protein, glycolysis inhibitors (2-DG, oxamate), pharmacological Hif1α inhibitor (YC-1) as epistasis","journal":"Cell stress & chaperones","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological epistasis placing Smurf1-Hif1α axis downstream of HSPA12A, single lab, in vitro only","pmids":["39349238"],"is_preprint":false},{"year":2024,"finding":"HSPA12A overexpression in cardiomyocytes activates mTOR and inhibits autophagy to enhance TLR4/MyD88/NF-κB-mediated inflammation; HSPA12A knockout protected against septic cardiomyopathy, and mTOR inhibition by rapamycin reversed HSPA12A-induced autophagy inhibition and inflammation.","method":"Hspa12a-/- mice (CLP sepsis model), HSPA12A OE in cardiomyocytes, mTOR/autophagy markers (LC3-II, p62), rapamycin epistasis, echocardiography, TUNEL/PI staining","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse model with cardiac phenotype plus pharmacological epistasis via rapamycin, single lab","pmids":["39642573"],"is_preprint":false},{"year":2021,"finding":"HSPA12A protects skeletal muscle from bupivacaine-induced myotoxicity by promoting PGC1α expression and nuclear localization, thereby maintaining mitochondrial contents and integrity; PGC1α inhibition (SR-18292) abolished HSPA12A-mediated protection.","method":"HSPA12A OE in C2c12 myoblasts, bupivacaine myotoxicity model in mice and in vitro, mitochondrial content/fragmentation assays, PGC1α nuclear fractionation, PGC1α inhibitor (SR-18292) epistasis","journal":"Toxicology and applied pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological epistasis placing PGC1α downstream of HSPA12A, in vitro and in vivo, single lab","pmids":["34793778"],"is_preprint":false}],"current_model":"HSPA12A is an atypical HSP70 family member that functions as a scaffolding/adaptor protein and intracellular chaperone: it interacts directly with diverse partners including PKM2, PGC-1α, p53/USP10, c-Myc, and SorLA to regulate their nuclear translocation, protein stability (via ubiquitin-proteasome pathways), and downstream transcriptional programs, thereby controlling glycolysis, lactylation-based epigenetic signaling, macrophage polarization, pyroptosis, fibroblast activation, and angiogenesis across multiple organ systems."},"narrative":{"teleology":[{"year":2018,"claim":"Establishing that HSPA12A functions as an adaptor promoting nuclear translocation of PKM2, this discovery linked HSPA12A to macrophage M1 polarization and hepatocyte steatosis in NASH, providing the first defined intracellular binding partner and cellular mechanism.","evidence":"Co-IP, nuclear fractionation, and Hspa12a KO mice on high-fat diet","pmids":["30455376"],"confidence":"High","gaps":["Direct binding interface between HSPA12A and PKM2 not mapped","Unclear whether HSPA12A chaperone ATPase activity is required for PKM2 translocation"]},{"year":2019,"claim":"Two studies broadened HSPA12A's partner repertoire: binding to SorLA's cytosolic domain in an ADP/ATP-dependent manner demonstrated canonical HSP70-like nucleotide-regulated interaction, while a PPARγ-HSPA12A positive feedback loop established HSPA12A's role in adipocyte differentiation.","evidence":"Pulldown and trafficking assays for SorLA binding; ChIP for PPARγ binding to Hspa12a promoter plus KO mouse adipogenesis studies","pmids":["30679749","30742088"],"confidence":"High","gaps":["Whether the ATPase cycle of HSPA12A is catalytically active or structurally vestigial remains unresolved","How HSPA12A promotes PPARγ expression at the molecular level is not defined"]},{"year":2020,"claim":"HSPA12A was shown to promote PGC-1α nuclear translocation in hepatocytes to suppress pyroptosis, and separately to interact with HRD1 to drive CD147 ubiquitination and degradation in RCC cells, establishing HSPA12A as a general scaffolding protein that bridges partners for both transcriptional activation and proteasomal degradation.","evidence":"Co-IP plus KO mice for PGC-1α–AOAH–Caspase-11 axis; MS-identified HSPA12A–HRD1 interaction with CD147 stability assays in RCC cells","pmids":["32332915","32754264"],"confidence":"High","gaps":["Whether HSPA12A simultaneously engages PGC-1α and HRD1 or these are cell-type-specific interactions is unknown","Structural basis of HSPA12A scaffolding is absent"]},{"year":2021,"claim":"HSPA12A was placed upstream of ERK/Akt signaling in endothelial barrier protection and confirmed to promote PGC-1α nuclear localization in skeletal muscle, extending its nuclear-translocation adaptor function to additional tissues.","evidence":"KO mice in acute lung injury plus ERK/Akt inhibitor epistasis in HUVECs; HSPA12A OE in myoblasts with PGC-1α inhibitor epistasis","pmids":["34343936","34793778"],"confidence":"Medium","gaps":["How HSPA12A activates ERK/Akt phosphorylation—direct kinase interaction or indirect—is not resolved","PGC-1α results rely on pharmacological epistasis without direct binding domain mapping"]},{"year":2022,"claim":"HSPA12A was linked to angiogenesis via p38/ERK–AP-1 signaling in endothelial cells, while upstream regulation of HSPA12A itself was revealed: SRSF11-dependent alternative splicing of exon 2 controls HSPA12A transcript stability and N-cadherin-driven colorectal cancer metastasis.","evidence":"KO mice post-MI with p38/ERK inhibitor epistasis for angiogenesis; UV-CLIP and minigene assays for SRSF11–HSPA12A splicing regulation","pmids":["35783189","36394206"],"confidence":"High","gaps":["Whether the exon 2-containing isoform has altered protein function versus only RNA stability effects is unclear","Direct HSPA12A–AP-1 interaction not demonstrated"]},{"year":2023,"claim":"A unifying metabolic theme emerged: HSPA12A suppresses hepatocyte glycolysis to reduce HMGB1 lactylation and exosomal secretion protecting against liver I/R injury, while in hippocampal neurons it sustains glycolysis via GSK3β inhibition for lactate-dependent neurogenesis—revealing tissue-specific directionality of HSPA12A's glycolytic regulation.","evidence":"Hepatocyte-specific HSPA12A OE/KO with HMGB1 lactylation and exosome assays; Hspa12a KO mice with CSF lactate measurement, BrdU labeling, and lactate rescue","pmids":["37441587","37580315"],"confidence":"High","gaps":["Mechanism by which HSPA12A inhibits GSK3β is not defined at the molecular level","How HSPA12A achieves opposite glycolytic effects in hepatocytes versus neurons is unexplained"]},{"year":2024,"claim":"Multiple 2024 studies solidified HSPA12A's scaffolding mechanism: it bridges p53 and USP10 to stabilize p53 and suppress cardiac fibrosis; it promotes Smurf1-dependent HIF-1α stabilization to maintain glycolysis in cardiomyocytes and renal tubular cells; and it drives c-Myc nuclear translocation and lactylation for renal recovery, while in septic cardiomyopathy it activates mTOR to inhibit autophagy.","evidence":"Co-IP for ternary HSPA12A–p53–USP10 complex with KO mice post-MI; HIF-1α stability assays with Smurf1 dependence in cardiomyocytes and HK-2 cells; Co-IP for HSPA12A–c-Myc with nuclear fractionation in TECs; KO mice in CLP sepsis model with rapamycin epistasis","pmids":["38219869","38421727","39277835","39349238","39642573"],"confidence":"High","gaps":["Whether HSPA12A directly binds Smurf1 or acts indirectly on HIF-1α stability is not established","Structural basis for simultaneous scaffolding of p53 and USP10 is unknown","How HSPA12A activates mTOR in cardiomyocytes is mechanistically undefined"]},{"year":null,"claim":"Key unresolved questions include: whether HSPA12A possesses functional ATPase activity, the structural basis of its multi-partner scaffolding, and the molecular determinants that produce opposing glycolytic effects across cell types.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of HSPA12A exists","ATPase activity has not been directly measured","Cell-type-specific partner selectivity mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,10,12]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,4,11,13]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,4,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,12]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,4,8,9,11,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,8,14]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,10,11]}],"complexes":[],"partners":["PKM2","PGC1A","SORLA","HRD1","TP53","USP10","MYC","SMURF1"],"other_free_text":[]},"mechanistic_narrative":"HSPA12A is an atypical HSP70 family member that functions primarily as a scaffolding and adaptor protein, promoting the nuclear translocation of transcription-related partners (PKM2, PGC-1α, c-Myc, AP-1) and regulating protein stability through the ubiquitin-proteasome system (bridging p53 with USP10 for deubiquitination; facilitating HRD1-mediated CD147 degradation; enhancing Smurf1-dependent HIF-1α stabilization) [PMID:30455376, PMID:32332915, PMID:38219869, PMID:38421727, PMID:39277835]. Through these interactions, HSPA12A controls glycolytic flux, lactate-driven protein lactylation (of HMGB1 and histones), and downstream transcriptional programs that govern macrophage polarization, pyroptosis, cardiac fibroblast activation, endothelial barrier integrity, angiogenesis, and tubular epithelial cell proliferation across liver, heart, kidney, and brain [PMID:37441587, PMID:35783189, PMID:34343936, PMID:39277835]. HSPA12A also participates in a positive feedback loop with PPARγ to drive adipocyte differentiation and sustains hippocampal neurogenesis by maintaining cerebral lactate homeostasis through GSK3β inhibition [PMID:30742088, PMID:37580315]. Alternative splicing of HSPA12A pre-mRNA is regulated by the PAK5–SRSF11 axis, with exon 2 retention yielding a transcript that stabilizes N-cadherin expression and promotes colorectal cancer metastasis [PMID:36394206]."},"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":147,"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":117,"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 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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":"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":"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":"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":13696,"output_tokens":4172,"usd":0.051834},"stage2":{"model":"claude-opus-4-6","input_tokens":7711,"output_tokens":2746,"usd":0.160807},"total_usd":0.212641,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"HSPA12A selectively binds to the cytosolic domain of SorLA (an amyloid precursor protein receptor) in an ADP/ATP-dependent manner via specific acidic residues in SorLA's cytosolic domain, acting as an adaptor protein that affects both endocytic speed and subcellular localization of SorLA.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, ADP/ATP-dependent binding assays, trafficking assays in cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction with functional consequence (trafficking), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30679749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In macrophages, HSPA12A directly interacts with PKM2 (M2 isoform of pyruvate kinase) and promotes its nuclear translocation, thereby driving M1 macrophage polarization and secretion of proinflammatory cytokines, which paracrinally induces hepatocyte steatosis in NASH.\",\n      \"method\": \"Co-immunoprecipitation, loss- and gain-of-function studies, nuclear fractionation, high-fat diet mouse model with Hspa12a knockout\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus KO mouse model with defined cellular phenotype and multiple orthogonal methods\",\n      \"pmids\": [\"30455376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HSPA12A directly interacts with PGC-1α and promotes its nuclear translocation in hepatocytes, thereby inducing AOAH expression which inactivates cytosolic LPS and suppresses Caspase-11-mediated hepatocyte pyroptosis (GSDMD cleavage).\",\n      \"method\": \"Co-immunoprecipitation, loss- and gain-of-function in primary hepatocytes, Hspa12a-/- mice, nuclear fractionation, AOAH overexpression rescue experiments\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction identified by Co-IP with functional rescue, KO mouse model, multiple orthogonal approaches\",\n      \"pmids\": [\"32332915\"],\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 to drive 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-/- mice on HFD, PPARγ inhibitor (GW9662) rescue, gain/loss-of-function in primary adipocytes\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP assay for direct promoter binding plus KO mouse model and pharmacological rescue\",\n      \"pmids\": [\"30742088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HSPA12A interacts with HRD1 ubiquitin E3 ligase in renal cell carcinoma (RCC) cells, promoting CD147 ubiquitination and proteasomal degradation, thereby reducing lactate export and glycolysis to suppress RCC cell migration.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, immunoblotting, cycloheximide/MG132 protein stability assays, CD147 overexpression rescue, wound healing and Transwell migration assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-identified interaction confirmed by Co-IP, mechanistic rescue with CD147 overexpression, 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 increases phosphorylation of ERKs and Akt, maintaining VE-cadherin expression and reducing VEGF expression, thereby preserving endothelial barrier integrity and protecting against LPS-induced acute lung injury; pharmacological inhibition of either ERKs or Akt abolishes these protective effects.\",\n      \"method\": \"HSPA12A KO mice (in vivo ALI model), HSPA12A overexpression in HUVECs, phosphorylation assays, ERK/Akt inhibitors as epistasis, permeability assays\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse phenotype plus pathway placement via pharmacological inhibitor epistasis, 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, which drives AP-1 phosphorylation and nuclear localization, increasing expression of VEGF, VEGFR2, and Ang-1; inhibition of p38 or ERK abolished HSPA12A-promoted angiogenesis.\",\n      \"method\": \"HSPA12A KO mice post-MI, HSPA12A overexpression in endothelial cells, phosphorylation assays, pharmacological inhibition of p38/ERK, tube formation/migration/proliferation assays\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with defined phenotype plus pathway placed by pharmacological epistasis, single lab\",\n      \"pmids\": [\"35783189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRSF11 regulates alternative splicing of HSPA12A pre-mRNA by directly binding a motif in exon 2 (shown by UV-CLIP and minigene assay); the HSPA12A transcript with exon 2 retention promotes RNA stability and increases N-cadherin expression, facilitating colorectal cancer metastasis. PAK5 phosphorylates SRSF11 at serine 287 to protect it from ubiquitination degradation, placing HSPA12A downstream in a PAK5/SRSF11/HSPA12A axis.\",\n      \"method\": \"UV crosslinking and immunoprecipitation (CLIP), minigene reporter assay, Co-IP, Phospho-tag SDS-PAGE, in vitro kinase assay, RNA-seq\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods including in vitro kinase assay, CLIP, and minigene validation in single rigorous study\",\n      \"pmids\": [\"36394206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HSPA12A overexpression suppresses glycolysis-generated lactate in hepatocytes, thereby reducing HMGB1 lactylation and its secretion in exosomes, which inhibits macrophage chemotaxis and inflammatory activation to protect against liver ischemia/reperfusion injury; HSPA12A knockout had opposite effects reversed by HMGB1 knockdown.\",\n      \"method\": \"Hepatocyte-specific HSPA12A overexpression, Hspa12a KO mice, Transwell chemotaxis assays, immunoprecipitation for lactylation, exosome HMGB1 measurement, HMGB1 knockdown rescue\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — hepatocyte-specific KO and OE in vivo and in vitro with molecular rescue (HMGB1 KD), multiple orthogonal methods\",\n      \"pmids\": [\"37441587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HSPA12A maintains cerebral lactate homeostasis by inhibiting GSK3β in hippocampal neurons to sustain glycolytic enzyme expression and lactate production; Hspa12a-/- mice showed mood instability and impaired adult hippocampal neurogenesis that were rescued by lactate administration.\",\n      \"method\": \"Hspa12a-/- mouse behavioral tests, CSF lactate measurement, BrdU labeling for neurogenesis, HSPA12A OE in primary hippocampal neurons, lactate rescue experiments\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with defined cellular phenotype and rescue by lactate, pathway placement via GSK3β, single lab\",\n      \"pmids\": [\"37580315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HSPA12A acts as a scaffolding protein binding both p53 and USP10 (ubiquitin specific protease 10) in cardiac fibroblasts, promoting USP10-mediated deubiquitination and stabilization of p53 protein, which then suppresses glycolysis and inhibits cardiac fibroblast activation and cardiac fibrosis.\",\n      \"method\": \"Co-immunoprecipitation-immunoblotting for HSPA12A-p53-USP10 ternary complex, cycloheximide/MG132 protein stability assays, Hspa12a KO mice post-MI, CF activation assays, Masson's trichrome staining\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ternary complex identified by Co-IP with functional consequence shown in KO mouse, protein stability mechanistically explained, multiple orthogonal methods\",\n      \"pmids\": [\"38219869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HSPA12A maintains aerobic glycolysis in cardiomyocytes during reperfusion by increasing Smurf1-mediated Hif1α protein stability, thereby upregulating glycolytic gene expression and sustaining Histone H3 lactylation; HSPA12A KO exacerbated MI/R-induced cardiomyocyte death and cardiac dysfunction.\",\n      \"method\": \"Hspa12a KO mice, gain/loss-of-function in cardiomyocytes, H3 lactylation assays, Hif1α protein stability assays (cycloheximide), Smurf1-dependent Hif1α stabilization, echocardiography\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with defined cardiac phenotype, molecular pathway placed by Smurf1-Hif1α axis, multiple orthogonal methods\",\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, enhancing c-Myc nuclear localization and lactylation (via Hif1α-dependent glycolysis-derived lactate), which drives proliferation-related gene expression and TEC proliferation to support renal recovery from ischemia/reperfusion injury.\",\n      \"method\": \"Co-immunoprecipitation for HSPA12A-c-Myc interaction, nuclear fractionation, c-Myc lactylation assays, Hif1α-dependent glycolysis experiments, Hspa12a KO mice post-KI/R, gain/loss-of-function in TEC\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction by Co-IP with nuclear localization consequence, KO mouse model, lactylation mechanistically linked, multiple orthogonal methods\",\n      \"pmids\": [\"39277835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HSPA12A promotes Smurf1-dependent Hif1α protein stability (not transcription) to increase aerobic glycolytic flux and drive TEC proliferation after hypoxia/reoxygenation; glycolysis inhibition or Hif1α pharmacological inhibition (YC-1) abolished HSPA12A-promoted proliferation.\",\n      \"method\": \"Loss/gain-of-function in HK-2 cells, Hif1α protein stability assays, qPCR for transcription vs. protein, glycolysis inhibitors (2-DG, oxamate), pharmacological Hif1α inhibitor (YC-1) as epistasis\",\n      \"journal\": \"Cell stress & chaperones\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological epistasis placing Smurf1-Hif1α axis downstream of HSPA12A, single lab, in vitro only\",\n      \"pmids\": [\"39349238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HSPA12A overexpression in cardiomyocytes activates mTOR and inhibits autophagy to enhance TLR4/MyD88/NF-κB-mediated inflammation; HSPA12A knockout protected against septic cardiomyopathy, and mTOR inhibition by rapamycin reversed HSPA12A-induced autophagy inhibition and inflammation.\",\n      \"method\": \"Hspa12a-/- mice (CLP sepsis model), HSPA12A OE in cardiomyocytes, mTOR/autophagy markers (LC3-II, p62), rapamycin epistasis, echocardiography, TUNEL/PI staining\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with cardiac phenotype plus pharmacological epistasis via rapamycin, single lab\",\n      \"pmids\": [\"39642573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HSPA12A protects skeletal muscle from bupivacaine-induced myotoxicity by promoting PGC1α expression and nuclear localization, thereby maintaining mitochondrial contents and integrity; PGC1α inhibition (SR-18292) abolished HSPA12A-mediated protection.\",\n      \"method\": \"HSPA12A OE in C2c12 myoblasts, bupivacaine myotoxicity model in mice and in vitro, mitochondrial content/fragmentation assays, PGC1α nuclear fractionation, PGC1α inhibitor (SR-18292) epistasis\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological epistasis placing PGC1α downstream of HSPA12A, in vitro and in vivo, single lab\",\n      \"pmids\": [\"34793778\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HSPA12A is an atypical HSP70 family member that functions as a scaffolding/adaptor protein and intracellular chaperone: it interacts directly with diverse partners including PKM2, PGC-1α, p53/USP10, c-Myc, and SorLA to regulate their nuclear translocation, protein stability (via ubiquitin-proteasome pathways), and downstream transcriptional programs, thereby controlling glycolysis, lactylation-based epigenetic signaling, macrophage polarization, pyroptosis, fibroblast activation, and angiogenesis across multiple organ systems.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HSPA12A is an atypical HSP70 family member that functions primarily as a scaffolding and adaptor protein, promoting the nuclear translocation of transcription-related partners (PKM2, PGC-1α, c-Myc, AP-1) and regulating protein stability through the ubiquitin-proteasome system (bridging p53 with USP10 for deubiquitination; facilitating HRD1-mediated CD147 degradation; enhancing Smurf1-dependent HIF-1α stabilization) [PMID:30455376, PMID:32332915, PMID:38219869, PMID:38421727, PMID:39277835]. Through these interactions, HSPA12A controls glycolytic flux, lactate-driven protein lactylation (of HMGB1 and histones), and downstream transcriptional programs that govern macrophage polarization, pyroptosis, cardiac fibroblast activation, endothelial barrier integrity, angiogenesis, and tubular epithelial cell proliferation across liver, heart, kidney, and brain [PMID:37441587, PMID:35783189, PMID:34343936, PMID:39277835]. HSPA12A also participates in a positive feedback loop with PPARγ to drive adipocyte differentiation and sustains hippocampal neurogenesis by maintaining cerebral lactate homeostasis through GSK3β inhibition [PMID:30742088, PMID:37580315]. Alternative splicing of HSPA12A pre-mRNA is regulated by the PAK5–SRSF11 axis, with exon 2 retention yielding a transcript that stabilizes N-cadherin expression and promotes colorectal cancer metastasis [PMID:36394206].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing that HSPA12A functions as an adaptor promoting nuclear translocation of PKM2, this discovery linked HSPA12A to macrophage M1 polarization and hepatocyte steatosis in NASH, providing the first defined intracellular binding partner and cellular mechanism.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, and Hspa12a KO mice on high-fat diet\",\n      \"pmids\": [\"30455376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface between HSPA12A and PKM2 not mapped\", \"Unclear whether HSPA12A chaperone ATPase activity is required for PKM2 translocation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two studies broadened HSPA12A's partner repertoire: binding to SorLA's cytosolic domain in an ADP/ATP-dependent manner demonstrated canonical HSP70-like nucleotide-regulated interaction, while a PPARγ-HSPA12A positive feedback loop established HSPA12A's role in adipocyte differentiation.\",\n      \"evidence\": \"Pulldown and trafficking assays for SorLA binding; ChIP for PPARγ binding to Hspa12a promoter plus KO mouse adipogenesis studies\",\n      \"pmids\": [\"30679749\", \"30742088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the ATPase cycle of HSPA12A is catalytically active or structurally vestigial remains unresolved\", \"How HSPA12A promotes PPARγ expression at the molecular level is not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"HSPA12A was shown to promote PGC-1α nuclear translocation in hepatocytes to suppress pyroptosis, and separately to interact with HRD1 to drive CD147 ubiquitination and degradation in RCC cells, establishing HSPA12A as a general scaffolding protein that bridges partners for both transcriptional activation and proteasomal degradation.\",\n      \"evidence\": \"Co-IP plus KO mice for PGC-1α–AOAH–Caspase-11 axis; MS-identified HSPA12A–HRD1 interaction with CD147 stability assays in RCC cells\",\n      \"pmids\": [\"32332915\", \"32754264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HSPA12A simultaneously engages PGC-1α and HRD1 or these are cell-type-specific interactions is unknown\", \"Structural basis of HSPA12A scaffolding is absent\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"HSPA12A was placed upstream of ERK/Akt signaling in endothelial barrier protection and confirmed to promote PGC-1α nuclear localization in skeletal muscle, extending its nuclear-translocation adaptor function to additional tissues.\",\n      \"evidence\": \"KO mice in acute lung injury plus ERK/Akt inhibitor epistasis in HUVECs; HSPA12A OE in myoblasts with PGC-1α inhibitor epistasis\",\n      \"pmids\": [\"34343936\", \"34793778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How HSPA12A activates ERK/Akt phosphorylation—direct kinase interaction or indirect—is not resolved\", \"PGC-1α results rely on pharmacological epistasis without direct binding domain mapping\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"HSPA12A was linked to angiogenesis via p38/ERK–AP-1 signaling in endothelial cells, while upstream regulation of HSPA12A itself was revealed: SRSF11-dependent alternative splicing of exon 2 controls HSPA12A transcript stability and N-cadherin-driven colorectal cancer metastasis.\",\n      \"evidence\": \"KO mice post-MI with p38/ERK inhibitor epistasis for angiogenesis; UV-CLIP and minigene assays for SRSF11–HSPA12A splicing regulation\",\n      \"pmids\": [\"35783189\", \"36394206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the exon 2-containing isoform has altered protein function versus only RNA stability effects is unclear\", \"Direct HSPA12A–AP-1 interaction not demonstrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A unifying metabolic theme emerged: HSPA12A suppresses hepatocyte glycolysis to reduce HMGB1 lactylation and exosomal secretion protecting against liver I/R injury, while in hippocampal neurons it sustains glycolysis via GSK3β inhibition for lactate-dependent neurogenesis—revealing tissue-specific directionality of HSPA12A's glycolytic regulation.\",\n      \"evidence\": \"Hepatocyte-specific HSPA12A OE/KO with HMGB1 lactylation and exosome assays; Hspa12a KO mice with CSF lactate measurement, BrdU labeling, and lactate rescue\",\n      \"pmids\": [\"37441587\", \"37580315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which HSPA12A inhibits GSK3β is not defined at the molecular level\", \"How HSPA12A achieves opposite glycolytic effects in hepatocytes versus neurons is unexplained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multiple 2024 studies solidified HSPA12A's scaffolding mechanism: it bridges p53 and USP10 to stabilize p53 and suppress cardiac fibrosis; it promotes Smurf1-dependent HIF-1α stabilization to maintain glycolysis in cardiomyocytes and renal tubular cells; and it drives c-Myc nuclear translocation and lactylation for renal recovery, while in septic cardiomyopathy it activates mTOR to inhibit autophagy.\",\n      \"evidence\": \"Co-IP for ternary HSPA12A–p53–USP10 complex with KO mice post-MI; HIF-1α stability assays with Smurf1 dependence in cardiomyocytes and HK-2 cells; Co-IP for HSPA12A–c-Myc with nuclear fractionation in TECs; KO mice in CLP sepsis model with rapamycin epistasis\",\n      \"pmids\": [\"38219869\", \"38421727\", \"39277835\", \"39349238\", \"39642573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HSPA12A directly binds Smurf1 or acts indirectly on HIF-1α stability is not established\", \"Structural basis for simultaneous scaffolding of p53 and USP10 is unknown\", \"How HSPA12A activates mTOR in cardiomyocytes is mechanistically undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: whether HSPA12A possesses functional ATPase activity, the structural basis of its multi-partner scaffolding, and the molecular determinants that produce opposing glycolytic effects across cell types.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of HSPA12A exists\", \"ATPase activity has not been directly measured\", \"Cell-type-specific partner selectivity mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 10, 12]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 4, 11, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 4, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 4, 8, 9, 11, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 8, 14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 10, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PKM2\", \"PGC1A\", \"SorLA\", \"HRD1\", \"TP53\", \"USP10\", \"MYC\", \"SMURF1\"],\n    \"other_free_text\": []\n  }\n}\n```"}