{"gene":"ABHD10","run_date":"2026-06-09T22:02:37","timeline":{"discoveries":[{"year":2019,"finding":"ABHD10 is a resident mitochondrial S-depalmitoylase that removes palmitoyl groups from peroxiredoxin-5 (PRDX5) at its nucleophilic active site cysteine residue, directly regulating PRDX5 antioxidant capacity and mitochondrial redox homeostasis.","method":"Mitochondrial-targeted APT inhibitor treatment, identification of PRDX5 as ABHD10 substrate, active site cysteine palmitoylation readout linked to antioxidant function","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional validation with inhibitors, substrate identification with mechanistic linkage to active site residue, replicated across multiple orthogonal approaches in one rigorous study","pmids":["31740833"],"is_preprint":false},{"year":2012,"finding":"ABHD10 is the enzyme responsible for deglucuronidation (hydrolysis) of mycophenolic acid acyl-glucuronide (AcMPAG) in human liver; purified from human liver cytosol by column chromatography, confirmed by amino acid sequence analysis, and recombinant ABHD10 expressed in Sf9 cells demonstrated this activity with Km of ~100.7 µM. Activity was inhibited by PMSF, AgNO3, CdCl2, CuCl2, bis-p-nitrophenylphosphate, and DTNB, consistent with a serine hydrolase mechanism.","method":"Enzyme purification from human liver cytosol, amino acid sequence analysis, recombinant expression in Sf9 cells with kinetic assay, chemical inhibition profile","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical purification to homogeneity, identity confirmed by sequencing, in vitro reconstitution with recombinant enzyme and kinetic characterization","pmids":["22294686"],"is_preprint":false},{"year":2014,"finding":"ABHD10 substantially catalyzes deglucuronidation of probenecid acyl glucuronide (PRAG) in human liver, whereas carboxylesterases do not; recombinant ABHD10 showed activity matching inhibition profiles of human liver homogenates, and ABHD10 suppresses net PRAG formation from probenecid via multiple UGT enzymes (UGT1A1, UGT1A9, UGT2B7).","method":"Recombinant ABHD10 enzyme assay, chemical inhibition comparison with human liver homogenates, PMSF-based inhibition of endogenous activity","journal":"Drug metabolism and disposition: the biological fate of chemicals","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant enzyme assay with inhibition profiling, single lab, two orthogonal comparisons (recombinant vs. liver homogenate)","pmids":["25217485"],"is_preprint":false},{"year":2012,"finding":"ABHD10 is a serine hydrolase; activity-based protein profiling (ABPP) identified it as a serine hydrolase target, and the aza-β-lactam ABL303 potently and selectively inactivated ABHD10 (IC50 ≈ 30 nM) in vitro and in living cells via covalent acylation of the enzyme's serine nucleophile.","method":"Competitive activity-based protein profiling (ABPP) in cell and tissue proteomes; medicinal chemistry optimization; in vitro and cell-based inhibition assays","journal":"Journal of the American Chemical Society","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ABPP with selective covalent inhibitor, validated in cells and in vitro, single lab","pmids":["22400490"],"is_preprint":false},{"year":2023,"finding":"The transcription factor ELK-3 directly binds to the ABHD10 promoter to inhibit its transactivation; TGFβ1 and EGF signaling induce ABHD10 downregulation via ELK-3, leading to enhanced S-palmitoylation of PRDX5 Cys100, increased oxidative stress, and disrupted hepatocyte function. Ectopic Abhd10 overexpression ameliorated liver damage in ALD model mice.","method":"Promoter binding assays (ELK-3 to ABHD10 promoter), in vitro cell signaling experiments, site-specific palmitoylation (Cys100) readout, in vivo mouse ALD model with Abhd10 overexpression","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding demonstrated, palmitoylation site identified, in vivo rescue experiment, single lab","pmids":["37400491"],"is_preprint":false},{"year":2025,"finding":"ABHD10 is a mitochondrial matrix S-depalmitoylase specifically expressed in testis that is essential for sperm mitochondrial sheath formation and male fertility; ABHD10 deficiency causes hyper-palmitoylation of SPATA19, GK2, PDHX, NDUFV1, and SDHB, and ABHD10 physically interacts with SPATA19, GK2, and PDHX as identified by co-immunoprecipitation and proximity labeling.","method":"HA-tagged knock-in mice, Abhd10-null mice, super-resolution fluorescence imaging, electron microscopy, mitochondrial proteomic analysis, mass spectrometry-based mitochondrial acyl-biotin exchange assay, co-immunoprecipitation, proximity labeling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — knockout mouse model with defined fertility phenotype, MS-based substrate identification with acyl-biotin exchange, reciprocal Co-IP and proximity labeling for physical interactions, multiple orthogonal methods","pmids":["41285782"],"is_preprint":false},{"year":2026,"finding":"ABHD10 interacts with KCMF1 as shown by co-immunoprecipitation, forming a complex that may regulate mitochondrial lipid metabolism; silencing ABHD10 in senescent cochlear cells reduced P21 and P16 levels, decreased ROS, improved mitochondrial membrane potential, and lowered lipid droplet formation and triglyceride/fatty acid levels.","method":"Co-immunoprecipitation (ABHD10–KCMF1), ABHD10 silencing in HEI-OC1 cells with senescence markers, ROS measurement, mitochondrial membrane potential assay, lipid droplet/lipid quantification","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP for interaction, loss-of-function with multiple cellular readouts, single lab","pmids":["42206676"],"is_preprint":false},{"year":2014,"finding":"A rocaglate-derived β-lactone inhibited serine hydrolase activity of ABHD10 both in vitro and in intact PC3 cells, as determined by activity-based protein profiling, confirming ABHD10 is an active serine hydrolase.","method":"Activity-based protein profiling (ABPP) in vitro and in PC3 cells","journal":"Journal of the American Chemical Society","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single ABPP readout, single lab, no mechanistic follow-up specific to ABHD10 function","pmids":["24447064"],"is_preprint":false}],"current_model":"ABHD10 is a mitochondrial matrix serine hydrolase that functions as an S-depalmitoylase: it removes palmitoyl groups from substrate proteins including peroxiredoxin-5 (PRDX5, at its active-site cysteine), SPATA19, GK2, and PDHX, thereby regulating mitochondrial redox homeostasis, sperm mitochondrial sheath formation, and male fertility; in the liver, ABHD10 also acts as an acyl-glucuronide hydrolase (deglucuronidase) for mycophenolic acid and probenecid acyl-glucuronides, and its expression is transcriptionally repressed by ELK-3 downstream of TGFβ1/EGF signaling."},"narrative":{"mechanistic_narrative":"ABHD10 is a serine hydrolase that operates as a protein S-depalmitoylase in the mitochondrial matrix, controlling mitochondrial redox homeostasis and lipid-related function across multiple tissues [PMID:31740833, PMID:41285782]. Its catalytic mechanism rests on a serine nucleophile, established by covalent serine-directed inhibitors and activity-based protein profiling that classify it as an active serine hydrolase [PMID:22400490]. In its depalmitoylase role, ABHD10 removes palmitoyl groups from peroxiredoxin-5 (PRDX5) at the active-site cysteine (Cys100), thereby preserving PRDX5 antioxidant capacity and limiting mitochondrial oxidative stress [PMID:31740833, PMID:37400491]. In testis, ABHD10 is a mitochondrial matrix depalmitoylase essential for sperm mitochondrial sheath formation and male fertility, acting on substrates including SPATA19, GK2, PDHX, NDUFV1, and SDHB, with direct physical interactions demonstrated for SPATA19, GK2, and PDHX [PMID:41285782]. Beyond its depalmitoylase activity, ABHD10 also functions in human liver as an acyl-glucuronide hydrolase, deglucuronidating mycophenolic acid acyl-glucuronide and probenecid acyl-glucuronide [PMID:22294686, PMID:25217485]. ABHD10 expression is transcriptionally repressed by ELK-3 downstream of TGFβ1/EGF signaling, linking signaling-driven loss of ABHD10 to increased PRDX5 palmitoylation and hepatocyte oxidative damage [PMID:37400491].","teleology":[{"year":2012,"claim":"Established the first defined enzymatic function of ABHD10 by identifying it as the liver enzyme that hydrolyzes mycophenolic acid acyl-glucuronide, resolving which protein clears this reactive metabolite.","evidence":"Purification from human liver cytosol, sequence confirmation, and recombinant expression in Sf9 cells with kinetic and chemical inhibition profiling","pmids":["22294686"],"confidence":"High","gaps":["Did not define catalytic residues or structure","Did not address whether deglucuronidation is the physiological role versus an in vitro activity"]},{"year":2012,"claim":"Confirmed ABHD10 is a bona fide serine hydrolase and provided a selective covalent inhibitor, supplying chemical tools to interrogate its activity in cells.","evidence":"Competitive activity-based protein profiling and aza-β-lactam (ABL303) covalent inactivation in vitro and in living cells","pmids":["22400490"],"confidence":"Medium","gaps":["Did not identify endogenous substrates","Single lab"]},{"year":2014,"claim":"Extended ABHD10's acyl-glucuronide hydrolase role to a second substrate class, showing it, rather than carboxylesterases, deglucuronidates probenecid acyl-glucuronide.","evidence":"Recombinant enzyme assay and chemical inhibition comparison against human liver homogenates","pmids":["25217485"],"confidence":"Medium","gaps":["Did not establish in vivo relevance","Single lab; relied on inhibition-profile matching rather than genetic knockout"]},{"year":2014,"claim":"Independently corroborated ABHD10 as an active serine hydrolase using a distinct inhibitor chemotype in intact cells.","evidence":"Rocaglate-derived β-lactone inhibition by ABPP in vitro and in PC3 cells","pmids":["24447064"],"confidence":"Low","gaps":["Single ABPP readout with no mechanistic follow-up specific to ABHD10 function","No substrate or pathway link"]},{"year":2019,"claim":"Reframed ABHD10 as a protein S-depalmitoylase by identifying PRDX5 active-site cysteine palmitoylation as a regulated substrate, connecting the enzyme to mitochondrial redox control.","evidence":"Mitochondrial-targeted depalmitoylase inhibition and PRDX5 substrate identification with active-site cysteine readout","pmids":["31740833"],"confidence":"High","gaps":["Did not enumerate the full substrate repertoire","Did not resolve how ABHD10 is targeted to specific palmitoylated cysteines"]},{"year":2023,"claim":"Placed ABHD10 within a signaling axis by showing ELK-3 directly represses its promoter downstream of TGFβ1/EGF, linking ABHD10 loss to PRDX5 Cys100 palmitoylation and liver injury.","evidence":"Promoter binding assays, site-specific palmitoylation readout, and Abhd10 overexpression rescue in an alcoholic liver disease mouse model","pmids":["37400491"],"confidence":"Medium","gaps":["Did not define upstream signaling kinetics of ELK-3 activation","Single lab"]},{"year":2025,"claim":"Defined an essential in vivo role for ABHD10 in spermatogenesis, identifying it as a testis mitochondrial matrix depalmitoylase acting on multiple sheath and metabolic substrates.","evidence":"Knock-in and knockout mice, super-resolution and electron microscopy, mitochondrial acyl-biotin exchange mass spectrometry, co-immunoprecipitation, and proximity labeling","pmids":["41285782"],"confidence":"High","gaps":["Mechanism by which substrate hyper-palmitoylation disrupts sheath assembly not fully resolved","Relative contribution of each substrate to the fertility phenotype unclear"]},{"year":2026,"claim":"Implicated ABHD10 in cellular senescence and mitochondrial lipid handling through a new interactor, broadening its functional context beyond redox and fertility.","evidence":"Co-immunoprecipitation of ABHD10–KCMF1 and ABHD10 silencing in HEI-OC1 cells with senescence, ROS, membrane potential, and lipid readouts","pmids":["42206676"],"confidence":"Medium","gaps":["Functional significance and directionality of the KCMF1 complex not defined","Single lab; correlative cellular readouts"]},{"year":null,"claim":"How a single mitochondrial matrix serine hydrolase reconciles distinct activities (protein S-depalmitoylation versus acyl-glucuronide hydrolysis) and selects substrates across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate or active-site recognition in the corpus","Mechanism of substrate selectivity across tissues unknown","Relationship between its cytosolic/liver glucuronide activity and matrix depalmitoylase activity not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,2,3]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,4]}],"complexes":[],"partners":["PRDX5","SPATA19","GK2","PDHX","KCMF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NUJ1","full_name":"Palmitoyl-protein thioesterase ABHD10, mitochondrial","aliases":["Acyl-protein thioesterase ABHD10","Alpha/beta hydrolase domain-containing protein 10","Abhydrolase domain-containing protein 10","Mycophenolic acid acyl-glucuronide esterase, mitochondrial"],"length_aa":306,"mass_kda":33.9,"function":"Acts as an acyl-protein thioesterase that hydrolyzes fatty acids from acylated residues in proteins (PubMed:31740833). Regulates the mitochondrial S-depalmitoylation of the nucleophilic active site residue of peroxiredoxin-5/PRDX5, a key antioxidant protein, therefore modulating mitochondrial antioxidant ability (PubMed:31740833). Also catalyzes the deglucuronidation of mycophenolic acid acyl-glucuronide, an active metabolite of the immunosuppressant drug mycophenolate (PubMed:22294686)","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q9NUJ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ABHD10","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"RTN4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ABHD10","total_profiled":1310},"omim":[{"mim_id":"618756","title":"ABHYDROLASE DOMAIN-CONTAINING PROTEIN 10, DEPALMITOYLASE; ABHD10","url":"https://www.omim.org/entry/618756"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ABHD10"},"hgnc":{"alias_symbol":["FLJ11342"],"prev_symbol":[]},"alphafold":{"accession":"Q9NUJ1","domains":[{"cath_id":"3.40.50.1820","chopping":"64-179_233-304","consensus_level":"high","plddt":97.291,"start":64,"end":304}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NUJ1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NUJ1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NUJ1-F1-predicted_aligned_error_v6.png","plddt_mean":86.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ABHD10","jax_strain_url":"https://www.jax.org/strain/search?query=ABHD10"},"sequence":{"accession":"Q9NUJ1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NUJ1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NUJ1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NUJ1"}},"corpus_meta":[{"pmid":"22813719","id":"PMC_22813719","title":"The emerging role of human esterases.","date":"2012","source":"Drug metabolism and pharmacokinetics","url":"https://pubmed.ncbi.nlm.nih.gov/22813719","citation_count":192,"is_preprint":false},{"pmid":"31740833","id":"PMC_31740833","title":"ABHD10 is an S-depalmitoylase affecting redox homeostasis through peroxiredoxin-5.","date":"2019","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/31740833","citation_count":111,"is_preprint":false},{"pmid":"22400490","id":"PMC_22400490","title":"Competitive activity-based protein profiling identifies aza-β-lactams as a versatile chemotype for serine hydrolase inhibition.","date":"2012","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/22400490","citation_count":45,"is_preprint":false},{"pmid":"22294686","id":"PMC_22294686","title":"Human α/β hydrolase domain containing 10 (ABHD10) is responsible enzyme for deglucuronidation of mycophenolic acid acyl-glucuronide in liver.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22294686","citation_count":33,"is_preprint":false},{"pmid":"24447064","id":"PMC_24447064","title":"Remodeling natural products: chemistry and serine hydrolase activity of a rocaglate-derived β-lactone.","date":"2014","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/24447064","citation_count":29,"is_preprint":false},{"pmid":"25633248","id":"PMC_25633248","title":"Facile synthesis of borofragments and their evaluation in activity-based protein profiling.","date":"2015","source":"Chemical communications (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25633248","citation_count":25,"is_preprint":false},{"pmid":"25217485","id":"PMC_25217485","title":"An orphan esterase ABHD10 modulates probenecid acyl glucuronidation in human liver.","date":"2014","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/25217485","citation_count":20,"is_preprint":false},{"pmid":"35978367","id":"PMC_35978367","title":"MiR-19b-3p regulated by BC002059/ABHD10 axis promotes cell apoptosis in myocardial infarction.","date":"2022","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/35978367","citation_count":7,"is_preprint":false},{"pmid":"37400491","id":"PMC_37400491","title":"The Elk-3 target Abhd10 ameliorates hepatotoxic injury and fibrosis in alcoholic liver disease.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/37400491","citation_count":5,"is_preprint":false},{"pmid":"26521872","id":"PMC_26521872","title":"[Role of Human Orphan Esterases in Drug-induced Toxicity].","date":"2015","source":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","url":"https://pubmed.ncbi.nlm.nih.gov/26521872","citation_count":5,"is_preprint":false},{"pmid":"41285782","id":"PMC_41285782","title":"The S-depalmitoylase ABHD10 is essential for sperm mitochondrial sheath formation and male fertility.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41285782","citation_count":0,"is_preprint":false},{"pmid":"42206676","id":"PMC_42206676","title":"The ABHD10-KCMF1 Complex Mitigates Cochlear Aging by Regulating Mitochondrial Lipid Metabolism.","date":"2026","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/42206676","citation_count":0,"is_preprint":false},{"pmid":"39486179","id":"PMC_39486179","title":"Use of mendelian randomization to assess the causal associations of circulating plasma proteins with 12-lead ECG parameters.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39486179","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8527,"output_tokens":2350,"usd":0.030416,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9402,"output_tokens":2876,"usd":0.059455,"stage2_stop_reason":"end_turn"},"total_usd":0.089871,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"ABHD10 is a resident mitochondrial S-depalmitoylase that removes palmitoyl groups from peroxiredoxin-5 (PRDX5) at its nucleophilic active site cysteine residue, directly regulating PRDX5 antioxidant capacity and mitochondrial redox homeostasis.\",\n      \"method\": \"Mitochondrial-targeted APT inhibitor treatment, identification of PRDX5 as ABHD10 substrate, active site cysteine palmitoylation readout linked to antioxidant function\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional validation with inhibitors, substrate identification with mechanistic linkage to active site residue, replicated across multiple orthogonal approaches in one rigorous study\",\n      \"pmids\": [\"31740833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ABHD10 is the enzyme responsible for deglucuronidation (hydrolysis) of mycophenolic acid acyl-glucuronide (AcMPAG) in human liver; purified from human liver cytosol by column chromatography, confirmed by amino acid sequence analysis, and recombinant ABHD10 expressed in Sf9 cells demonstrated this activity with Km of ~100.7 µM. Activity was inhibited by PMSF, AgNO3, CdCl2, CuCl2, bis-p-nitrophenylphosphate, and DTNB, consistent with a serine hydrolase mechanism.\",\n      \"method\": \"Enzyme purification from human liver cytosol, amino acid sequence analysis, recombinant expression in Sf9 cells with kinetic assay, chemical inhibition profile\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical purification to homogeneity, identity confirmed by sequencing, in vitro reconstitution with recombinant enzyme and kinetic characterization\",\n      \"pmids\": [\"22294686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ABHD10 substantially catalyzes deglucuronidation of probenecid acyl glucuronide (PRAG) in human liver, whereas carboxylesterases do not; recombinant ABHD10 showed activity matching inhibition profiles of human liver homogenates, and ABHD10 suppresses net PRAG formation from probenecid via multiple UGT enzymes (UGT1A1, UGT1A9, UGT2B7).\",\n      \"method\": \"Recombinant ABHD10 enzyme assay, chemical inhibition comparison with human liver homogenates, PMSF-based inhibition of endogenous activity\",\n      \"journal\": \"Drug metabolism and disposition: the biological fate of chemicals\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant enzyme assay with inhibition profiling, single lab, two orthogonal comparisons (recombinant vs. liver homogenate)\",\n      \"pmids\": [\"25217485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ABHD10 is a serine hydrolase; activity-based protein profiling (ABPP) identified it as a serine hydrolase target, and the aza-β-lactam ABL303 potently and selectively inactivated ABHD10 (IC50 ≈ 30 nM) in vitro and in living cells via covalent acylation of the enzyme's serine nucleophile.\",\n      \"method\": \"Competitive activity-based protein profiling (ABPP) in cell and tissue proteomes; medicinal chemistry optimization; in vitro and cell-based inhibition assays\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ABPP with selective covalent inhibitor, validated in cells and in vitro, single lab\",\n      \"pmids\": [\"22400490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The transcription factor ELK-3 directly binds to the ABHD10 promoter to inhibit its transactivation; TGFβ1 and EGF signaling induce ABHD10 downregulation via ELK-3, leading to enhanced S-palmitoylation of PRDX5 Cys100, increased oxidative stress, and disrupted hepatocyte function. Ectopic Abhd10 overexpression ameliorated liver damage in ALD model mice.\",\n      \"method\": \"Promoter binding assays (ELK-3 to ABHD10 promoter), in vitro cell signaling experiments, site-specific palmitoylation (Cys100) readout, in vivo mouse ALD model with Abhd10 overexpression\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding demonstrated, palmitoylation site identified, in vivo rescue experiment, single lab\",\n      \"pmids\": [\"37400491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ABHD10 is a mitochondrial matrix S-depalmitoylase specifically expressed in testis that is essential for sperm mitochondrial sheath formation and male fertility; ABHD10 deficiency causes hyper-palmitoylation of SPATA19, GK2, PDHX, NDUFV1, and SDHB, and ABHD10 physically interacts with SPATA19, GK2, and PDHX as identified by co-immunoprecipitation and proximity labeling.\",\n      \"method\": \"HA-tagged knock-in mice, Abhd10-null mice, super-resolution fluorescence imaging, electron microscopy, mitochondrial proteomic analysis, mass spectrometry-based mitochondrial acyl-biotin exchange assay, co-immunoprecipitation, proximity labeling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — knockout mouse model with defined fertility phenotype, MS-based substrate identification with acyl-biotin exchange, reciprocal Co-IP and proximity labeling for physical interactions, multiple orthogonal methods\",\n      \"pmids\": [\"41285782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ABHD10 interacts with KCMF1 as shown by co-immunoprecipitation, forming a complex that may regulate mitochondrial lipid metabolism; silencing ABHD10 in senescent cochlear cells reduced P21 and P16 levels, decreased ROS, improved mitochondrial membrane potential, and lowered lipid droplet formation and triglyceride/fatty acid levels.\",\n      \"method\": \"Co-immunoprecipitation (ABHD10–KCMF1), ABHD10 silencing in HEI-OC1 cells with senescence markers, ROS measurement, mitochondrial membrane potential assay, lipid droplet/lipid quantification\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP for interaction, loss-of-function with multiple cellular readouts, single lab\",\n      \"pmids\": [\"42206676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A rocaglate-derived β-lactone inhibited serine hydrolase activity of ABHD10 both in vitro and in intact PC3 cells, as determined by activity-based protein profiling, confirming ABHD10 is an active serine hydrolase.\",\n      \"method\": \"Activity-based protein profiling (ABPP) in vitro and in PC3 cells\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single ABPP readout, single lab, no mechanistic follow-up specific to ABHD10 function\",\n      \"pmids\": [\"24447064\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ABHD10 is a mitochondrial matrix serine hydrolase that functions as an S-depalmitoylase: it removes palmitoyl groups from substrate proteins including peroxiredoxin-5 (PRDX5, at its active-site cysteine), SPATA19, GK2, and PDHX, thereby regulating mitochondrial redox homeostasis, sperm mitochondrial sheath formation, and male fertility; in the liver, ABHD10 also acts as an acyl-glucuronide hydrolase (deglucuronidase) for mycophenolic acid and probenecid acyl-glucuronides, and its expression is transcriptionally repressed by ELK-3 downstream of TGFβ1/EGF signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ABHD10 is a serine hydrolase that operates as a protein S-depalmitoylase in the mitochondrial matrix, controlling mitochondrial redox homeostasis and lipid-related function across multiple tissues [#0, #5]. Its catalytic mechanism rests on a serine nucleophile, established by covalent serine-directed inhibitors and activity-based protein profiling that classify it as an active serine hydrolase [#3]. In its depalmitoylase role, ABHD10 removes palmitoyl groups from peroxiredoxin-5 (PRDX5) at the active-site cysteine (Cys100), thereby preserving PRDX5 antioxidant capacity and limiting mitochondrial oxidative stress [#0, #4]. In testis, ABHD10 is a mitochondrial matrix depalmitoylase essential for sperm mitochondrial sheath formation and male fertility, acting on substrates including SPATA19, GK2, PDHX, NDUFV1, and SDHB, with direct physical interactions demonstrated for SPATA19, GK2, and PDHX [#5]. Beyond its depalmitoylase activity, ABHD10 also functions in human liver as an acyl-glucuronide hydrolase, deglucuronidating mycophenolic acid acyl-glucuronide and probenecid acyl-glucuronide [#1, #2]. ABHD10 expression is transcriptionally repressed by ELK-3 downstream of TGFβ1/EGF signaling, linking signaling-driven loss of ABHD10 to increased PRDX5 palmitoylation and hepatocyte oxidative damage [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the first defined enzymatic function of ABHD10 by identifying it as the liver enzyme that hydrolyzes mycophenolic acid acyl-glucuronide, resolving which protein clears this reactive metabolite.\",\n      \"evidence\": \"Purification from human liver cytosol, sequence confirmation, and recombinant expression in Sf9 cells with kinetic and chemical inhibition profiling\",\n      \"pmids\": [\"22294686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define catalytic residues or structure\", \"Did not address whether deglucuronidation is the physiological role versus an in vitro activity\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Confirmed ABHD10 is a bona fide serine hydrolase and provided a selective covalent inhibitor, supplying chemical tools to interrogate its activity in cells.\",\n      \"evidence\": \"Competitive activity-based protein profiling and aza-β-lactam (ABL303) covalent inactivation in vitro and in living cells\",\n      \"pmids\": [\"22400490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify endogenous substrates\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended ABHD10's acyl-glucuronide hydrolase role to a second substrate class, showing it, rather than carboxylesterases, deglucuronidates probenecid acyl-glucuronide.\",\n      \"evidence\": \"Recombinant enzyme assay and chemical inhibition comparison against human liver homogenates\",\n      \"pmids\": [\"25217485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish in vivo relevance\", \"Single lab; relied on inhibition-profile matching rather than genetic knockout\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Independently corroborated ABHD10 as an active serine hydrolase using a distinct inhibitor chemotype in intact cells.\",\n      \"evidence\": \"Rocaglate-derived β-lactone inhibition by ABPP in vitro and in PC3 cells\",\n      \"pmids\": [\"24447064\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single ABPP readout with no mechanistic follow-up specific to ABHD10 function\", \"No substrate or pathway link\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reframed ABHD10 as a protein S-depalmitoylase by identifying PRDX5 active-site cysteine palmitoylation as a regulated substrate, connecting the enzyme to mitochondrial redox control.\",\n      \"evidence\": \"Mitochondrial-targeted depalmitoylase inhibition and PRDX5 substrate identification with active-site cysteine readout\",\n      \"pmids\": [\"31740833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not enumerate the full substrate repertoire\", \"Did not resolve how ABHD10 is targeted to specific palmitoylated cysteines\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed ABHD10 within a signaling axis by showing ELK-3 directly represses its promoter downstream of TGFβ1/EGF, linking ABHD10 loss to PRDX5 Cys100 palmitoylation and liver injury.\",\n      \"evidence\": \"Promoter binding assays, site-specific palmitoylation readout, and Abhd10 overexpression rescue in an alcoholic liver disease mouse model\",\n      \"pmids\": [\"37400491\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define upstream signaling kinetics of ELK-3 activation\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined an essential in vivo role for ABHD10 in spermatogenesis, identifying it as a testis mitochondrial matrix depalmitoylase acting on multiple sheath and metabolic substrates.\",\n      \"evidence\": \"Knock-in and knockout mice, super-resolution and electron microscopy, mitochondrial acyl-biotin exchange mass spectrometry, co-immunoprecipitation, and proximity labeling\",\n      \"pmids\": [\"41285782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which substrate hyper-palmitoylation disrupts sheath assembly not fully resolved\", \"Relative contribution of each substrate to the fertility phenotype unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated ABHD10 in cellular senescence and mitochondrial lipid handling through a new interactor, broadening its functional context beyond redox and fertility.\",\n      \"evidence\": \"Co-immunoprecipitation of ABHD10–KCMF1 and ABHD10 silencing in HEI-OC1 cells with senescence, ROS, membrane potential, and lipid readouts\",\n      \"pmids\": [\"42206676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance and directionality of the KCMF1 complex not defined\", \"Single lab; correlative cellular readouts\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single mitochondrial matrix serine hydrolase reconciles distinct activities (protein S-depalmitoylation versus acyl-glucuronide hydrolysis) and selects substrates across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate or active-site recognition in the corpus\", \"Mechanism of substrate selectivity across tissues unknown\", \"Relationship between its cytosolic/liver glucuronide activity and matrix depalmitoylase activity not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PRDX5\", \"SPATA19\", \"GK2\", \"PDHX\", \"KCMF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}