{"gene":"HDAC11","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2002,"finding":"HDAC11 encodes a 347-residue, 39-kDa nuclear protein with histone deacetylase activity in vitro that is inhibited by trapoxin; epitope-tagged HDAC11 co-immunoprecipitates with HDAC6, indicating it resides in protein complexes containing HDAC6.","method":"In vitro deacetylase activity assay, trapoxin inhibition, Co-immunoprecipitation, nuclear localization by epitope-tag imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro enzymatic assay with inhibitor validation plus Co-IP, founding paper replicated by many subsequent studies","pmids":["11948178"],"is_preprint":false},{"year":2008,"finding":"HDAC11 negatively regulates IL-10 gene expression in antigen-presenting cells (APCs) by associating with the IL-10 promoter chromatin, thereby promoting inflammatory APC phenotype and suppressing immune tolerance.","method":"HDAC11 overexpression and siRNA knockdown in APCs, IL-10 expression assays, chromatin immunoprecipitation (ChIP) at the IL-10 promoter, T cell activation assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function with ChIP validation, replicated across multiple subsequent studies","pmids":["19011628"],"is_preprint":false},{"year":2014,"finding":"HDAC6 (a cytoplasmic protein) and HDAC11 (a nuclear protein) are both recruited to the IL-10 gene promoter in APCs, but with divergent transcriptional effects: HDAC11 represses IL-10 while HDAC6 acts as a transcriptional activator; the two HDACs physically associate.","method":"ChIP showing co-recruitment of HDAC6 and HDAC11 to the IL-10 promoter, co-immunoprecipitation, siRNA knockdown of each HDAC","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and ChIP in single lab with two orthogonal methods","pmids":["24747960"],"is_preprint":false},{"year":2019,"finding":"HDAC11 functions as an efficient lysine defatty-acylase (>10,000-fold more efficient than its deacetylase activity) and defatty-acylates SHMT2 at a specific lysine residue; this modification does not affect SHMT2 enzymatic activity but regulates type I IFN receptor ubiquitination and cell-surface levels, thereby suppressing type I IFN signaling in cells and mice.","method":"In vitro biochemical deacylase assay, SILAC proteomics for substrate identification, biochemical validation of SHMT2 as substrate, HDAC11 depletion in cells and mice with IFN signaling readouts","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with kinetic comparison, proteomics-based substrate identification, and in vivo validation in one rigorous study","pmids":["30819897"],"is_preprint":false},{"year":2019,"finding":"HDAC11 represses HBV cccDNA transcription by deacetylating cccDNA-bound histone H3, specifically reducing H3K9ac and H3K27ac marks on cccDNA; this restricts HBV replication without affecting cccDNA production.","method":"ChIP assay on cccDNA-bound histones, HDAC11 overexpression/knockdown in HBV-transfected cells, HBV replication assays","journal":"Antiviral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional replication readout, single lab, two orthogonal methods","pmids":["31600533"],"is_preprint":false},{"year":2010,"finding":"HDAC11 binds Cdt1 (and does so more efficiently in the presence of Geminin) at replication origins during S-phase, inhibiting Cdt1-induced chromatin decondensation and MCM loading, thereby suppressing re-replication; this is counteracted by HBO1 HAT activity in G1.","method":"Co-immunoprecipitation of HDAC11 with Cdt1/Geminin, ChIP at replication origins, chromatin decondensation assays, re-replication assays","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and ChIP with functional re-replication readout, single lab","pmids":["20980834"],"is_preprint":false},{"year":2011,"finding":"HDAC11 regulates OX40 ligand (OX40L) expression in Hodgkin lymphoma cells; siRNA-mediated depletion of HDAC11 upregulates OX40L surface expression, increases TNF-α and IL-17 production, and induces apoptosis.","method":"siRNA knockdown of HDAC11, flow cytometry for OX40L surface expression, cytokine measurement in supernatants","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with multiple phenotypic readouts, single lab","pmids":["21239696"],"is_preprint":false},{"year":2013,"finding":"HDAC11 binds the promoter region of the PAI-1 gene in a gender-specific manner (regulated by male hormone/testosterone/dihydrotestosterone); I/R injury or LPS causes HDAC11 to dissociate from the PAI-1 promoter, increasing local histone H3 acetylation and PAI-1 expression.","method":"ChIP assay showing HDAC11 binding to PAI-1 promoter, orchiectomy/DHT experiments, HDAC11 gene silencing with PAI-1 expression readout","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with loss-of-function validation, single lab","pmids":["23657855"],"is_preprint":false},{"year":2017,"finding":"HDAC11 is present at the Eomes and Tbet gene promoters in resting T cells (shown by ChIP) and dissociates upon T-cell activation; loss of HDAC11 increases Eomes and Tbet expression, enhancing T cell effector functions, cytokine production, and proliferation, while HDAC11 overexpression suppresses these genes.","method":"ChIP at Eomes/Tbet promoters, HDAC11 KO and transgenic overexpression mouse models, cytokine and transcription factor expression assays, in vivo GVHD model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP with KO and OE mouse models, multiple orthogonal readouts replicated in vivo","pmids":["28550044"],"is_preprint":false},{"year":2017,"finding":"HDAC11 suppresses myoblast differentiation in a catalytic-activity-dependent manner; wild-type HDAC11 inhibits MyoD-dependent transcription of MEF2C and Myogenin by reducing histone acetylation near E-boxes at their promoters, whereas a catalytically inactive mutant (H142/143A) does not impede differentiation.","method":"Ectopic expression of WT and catalytically inactive HDAC11 mutant in C2C12 myoblasts, MyoD-dependent promoter activity assays (luciferase), histone acetylation ChIP at MEF2C and MYOG promoters","journal":"Molecules and cells","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis paired with promoter activity and ChIP assays in single study","pmids":["28927261"],"is_preprint":false},{"year":2017,"finding":"HDAC11 controls CCL2 (MCP-1) gene expression by enabling binding of the transcription factor PU.1 to the CCL2 promoter; loss of HDAC11 reduces CCL2-driven monocyte/DC infiltration into the CNS and ameliorates EAE severity.","method":"HDAC11 KO mouse model, EAE (MS model), ChIP/promoter analysis of CCL2, immune cell infiltration analysis","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with ChIP-based promoter mechanism, single lab","pmids":["30456376"],"is_preprint":false},{"year":2018,"finding":"HDAC11 catalytic activity suppresses the brown adipose tissue (BAT) transcriptional program through physical association with BRD2, a bromodomain acetyl-histone-binding protein; HDAC11 deletion in mice stimulates BAT formation, beiging of WAT, and enhances thermogenic potential.","method":"HDAC11 KO mouse model, ex vivo and cell-based assays showing HDAC11-BRD2 physical interaction (Co-IP), β-adrenergic receptor signaling assays, UCP1 expression readouts","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with Co-IP establishing BRD2 interaction plus multiple cellular and in vivo readouts, single lab but multiple orthogonal methods","pmids":["30089714"],"is_preprint":false},{"year":2018,"finding":"HDAC11 deficiency in mice confers resistance to high-fat diet-induced obesity; mechanistically, HDAC11 depletion boosts UCP1 expression and thermogenic capacity in BAT and activates the adiponectin-AdipoR-AMPK pathway in the liver.","method":"HDAC11 KO mouse model on HFD, metabolic phenotyping, UCP1 expression assays, AMPK pathway analysis","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with metabolic phenotyping, single lab","pmids":["29958910"],"is_preprint":false},{"year":2018,"finding":"HDAC11 forms a complex with E4BP4 transcription factor in cardiac CD4+ T cells and restricts E4BP4 binding to the IL-13 promoter, thereby repressing IL-13 transcription; reconstitution of HDAC11 in myocarditis T cells reduced IL-13 expression.","method":"Co-immunoprecipitation of HDAC11–E4BP4 complex, HDAC11 reconstitution and inhibition in patient-derived CD4+ T cells, IL-13 expression assays","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and gain/loss-of-function in primary cells, single lab","pmids":["30063898"],"is_preprint":false},{"year":2019,"finding":"USP25 deubiquitinates HDAC11, stabilizing it; cigarette smoke extract (CSE) promotes USP25 ubiquitination and degradation, thereby reducing HDAC11 protein levels (without affecting HDAC11 transcript), increasing bacterial load; USP25–HDAC11 interaction demonstrated by Co-IP.","method":"Co-immunoprecipitation of USP25 and HDAC11, CSE treatment with protein stability assays, siRNA/OE of USP25, bacterial load assay","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with functional validation, single lab","pmids":["31746627"],"is_preprint":false},{"year":2020,"finding":"HDAC11 inhibition in mouse oocytes (by specific inhibitor JB3-22) increases α-tubulin acetylation and H4K16 acetylation, disrupts spindle organization, causes chromosome misalignment, impairs kinetochore-microtubule attachment and spindle assembly checkpoint, thereby blocking meiotic progression.","method":"HDAC11-specific inhibitor (JB3-22) treatment of mouse oocytes, immunofluorescence for spindle/chromosome/kinetochore markers, acetylation level measurement","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with multiple orthogonal cellular readouts, single lab","pmids":["31910069"],"is_preprint":false},{"year":2020,"finding":"HDAC11 depletion in HCC increases histone acetylation at the LKB1 promoter, activating LKB1 transcription and thus the AMPK signaling pathway, which inhibits glycolysis and suppresses cancer stemness; conditional HDAC11 KO mice showed reduced hepatocellular tumorigenesis.","method":"Conditional KO mouse model, ChIP at LKB1 promoter, AMPK/glycolysis pathway analysis, stemness assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with ChIP mechanism, single lab","pmids":["33602787"],"is_preprint":false},{"year":2020,"finding":"HDAC11 is localized in skeletal muscle mitochondria; its genetic deficiency enhances mitochondrial fatty acid β-oxidation through activating the AMPK-acetyl-CoA carboxylase pathway, reduces acylcarnitine levels, increases oxidative myofibers, and improves muscle fatigue resistance and strength.","method":"HDAC11 KO mouse model, mitochondrial fractionation/localization by imaging, AMPK-ACC pathway assays, metabolomics (acylcarnitines), fiber-type analysis","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with subcellular fractionation and multiple metabolic/functional readouts, single lab","pmids":["32563202"],"is_preprint":false},{"year":2021,"finding":"HDAC11 forms a complex with ERG and decreases ERG acetylation levels; HDAC11 knockdown mitigates TNF-α-induced pyroptosis via suppression of both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways in vascular endothelial cells.","method":"Co-immunoprecipitation of HDAC11 with ERG, acetylation assays of ERG, siRNA knockdown of HDAC11/GSDME in HUVECs, pyroptosis markers (caspase-1, caspase-3, GSDMD, GSDME, LDH, PI staining)","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and siRNA KD with multiple pyroptosis readouts, single lab","pmids":["35279683"],"is_preprint":false},{"year":2021,"finding":"HDAC11 is recruited to the C/EBPβ gene promoter in MDSCs (shown by ChIP); loss of HDAC11 upregulates C/EBPβ, leading to elevated arginase activity and NO production that enhance MDSC suppressive function.","method":"ChIP showing HDAC11 at C/EBPβ promoter in WT MDSCs, HDAC11 KO mouse-derived MDSCs, arginase activity and iNOS/NO assays","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with KO mouse functional readouts, single lab","pmids":["33866588"],"is_preprint":false},{"year":2021,"finding":"March1 (an E3 ubiquitin ligase) directly ubiquitinates HDAC11, promoting its degradation; HDAC11 forms a complex with transcription factor KLF4 to repress OX40L gene promoter activity; loss of HDAC11 (via March1-induced degradation) de-represses OX40L expression.","method":"Co-immunoprecipitation, immunofluorescence co-localization, luciferase promoter assay, ubiquitination assay, KLF4–HDAC11 complex detection","journal":"Journal of asthma and allergy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with promoter luciferase, single lab","pmids":["34385821"],"is_preprint":false},{"year":2022,"finding":"HDAC11 negatively regulates Nos2 (iNOS) expression in macrophages through its association with STAT3 (which acts as a scaffold protein anchoring HDAC11 to the Nos2 promoter); HDAC11 deficiency increases H3/H4 acetylation at the Nos2 promoter, boosting iNOS and NO-mediated antifungal killing.","method":"ChIP at Nos2 promoter, Co-IP of HDAC11 with STAT3, HDAC11 KO mouse model, fungal killing assays, HDAC11 inhibitor (FT895) in mouse and human cells","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP + Co-IP + KO mouse + pharmacological inhibition with in vivo and in vitro validation in single study","pmids":["36087429"],"is_preprint":false},{"year":2023,"finding":"HDAC11 acts as the eraser of lysine butyrylation (Kbu) on HSP90 at K754; KAT8 is the writer of this modification; SDCBP increases Kbu on HSP90 by competitively binding to HDAC11, preventing its eraser activity, leading to HSP90 overexpression and chemoresistance.","method":"Butyrylome profiling MS, gain/loss-of-function experiments, in vitro deacylase assays identifying HDAC11 as Kbu eraser for HSP90 K754, Co-IP of SDCBP–HDAC11","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — MS substrate identification plus in vitro enzymatic assay and Co-IP, single lab","pmids":["37460462"],"is_preprint":false},{"year":2023,"finding":"HDAC11 demyristoylates gravin-α (AKAP12); HDAC11 inhibition preserves gravin-α myristoylation, enabling β-adrenergic receptor signaling that induces UCP1 expression via a biphasic mechanism: an acute PKA-independent post-transcriptional response and a delayed PKA-dependent transcriptional response; adipocyte-specific HDAC11 deletion robustly induces UCP1 in adipose tissue and elevates body temperature.","method":"Adipocyte-specific HDAC11 KO mice, HDAC11-selective inhibitor FT895 in vivo and ex vivo (human AT), gravin-α myristoylation assays, UCP1 expression (protein/mRNA), PKA activity assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — tissue-specific KO + pharmacological inhibition + substrate myristoylation assays + multiple mechanistic readouts in one study","pmids":["37607030"],"is_preprint":false},{"year":2017,"finding":"HDAC11 is synaptic-enriched (not exclusively nuclear/cytoplasmic as previously reported) in brain tissue; in HDAC11 KO mice, loss of HDAC11 selectively decreases Fez1 expression in the hippocampus in an age-dependent and brain-region-specific manner.","method":"Subcellular fractionation showing synaptic enrichment, HDAC11 KO mouse brain analysis, Fez1 expression in cortical/cerebellar/hippocampal regions","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation-based localization and KO mouse with region-specific readout, single lab","pmids":["28928414"],"is_preprint":false},{"year":2017,"finding":"VDR (vitamin D receptor) forms a complex with HDAC11 in intestinal epithelial cells under VitD-sufficient conditions; in VitD-deficient conditions, HDAC11 binding to tight junction protein promoters increases, repressing their transcription and impairing barrier function; calcitriol abolishes this repressive HDAC11 promoter binding.","method":"Co-immunoprecipitation of VDR–HDAC11, ChIP at tight junction protein promoters, calcitriol treatment, epithelial barrier function assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP with functional readout, single lab","pmids":["28938596"],"is_preprint":false},{"year":2025,"finding":"HDAC11 deacetylates BRAF at K680, suppressing BRAF kinase activity and reducing cell proliferation; proteomics-based mutant trapping identified BRAF among 64 putative HDAC11 substrates.","method":"Proteomics mutant trapping to identify substrates, biochemical deacetylation assay of BRAF K680, kinase activity assay, cell proliferation assay","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — proteomics substrate identification plus in vitro enzymatic and kinase activity validation, single lab","pmids":["41273269"],"is_preprint":false},{"year":2025,"finding":"HDAC11 deacetylates TPI1 (triosephosphate isomerase 1) at K69, stabilizing TPI1 by attenuating K48-linked polyubiquitination; this stabilization promotes fibroblast-to-myofibroblast differentiation, proliferation, and migration in pulmonary fibrosis; TGF-β1 enhances this HDAC11-mediated deacetylation.","method":"In vitro deacetylation assay, site-specific mutagenesis (K69), ubiquitination assay, TGF-β1 stimulation in fibroblasts, KO mice and HDAC11 inhibitor (FT895) in bleomycin fibrosis model","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic + mutagenesis + ubiquitination assay + in vivo model, single lab","pmids":["41112094"],"is_preprint":false},{"year":2025,"finding":"HDAC11 deacetylates Parkin at K76, promoting Parkin ubiquitination and degradation; this impairs mitophagy and drives pro-fibrotic M2 macrophage polarization and macrophage-myofibroblast transition in idiopathic pulmonary fibrosis; adoptive transfer of HDAC11-deficient macrophages attenuates fibrosis.","method":"Site-specific deacetylation assay (Parkin K76), ubiquitination assay, HDAC11 KO mouse and macrophage adoptive transfer, mitophagy assays, fibrosis histology","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic assay at specific site + KO mouse adoptive transfer, single lab","pmids":["41997918"],"is_preprint":false},{"year":2026,"finding":"HDAC11 interacts with the NuRD (MTA3) complex through its N-terminal region; this complex transcriptionally represses TGFB1, thereby inhibiting HCC metastasis; HDAC11 silencing increases TGFB1 expression and metastatic potential, which is reversed by concurrent TGFB1 knockdown.","method":"Mass spectrometry identifying HDAC11-NuRD(MTA3) interaction, Co-IP and GST pull-down of HDAC11 N-terminal region with MTA3, transcriptomic analysis, in vitro and in vivo metastasis assays","journal":"Clinical epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS + Co-IP + GST pull-down + in vivo rescue experiment, single lab","pmids":["41547814"],"is_preprint":false},{"year":2026,"finding":"HDAC11 regulates RNA splicing via de-fatty acylation (de-myristoylation) of the spliceosomal protein SF3B2 at K10; a de-myristoylation mimetic mutant (K10R) exhibits altered pre-mRNA binding and promotes alternative splicing toward the AR-v7 variant in HCC cells in a cell-type-specific manner.","method":"Metabolic labeling, mass spectrometry, click chemistry, in vitro deacylase assay establishing SF3B2 K10 as direct HDAC11 substrate, SF3B2 K10R mutagenesis, AR splicing isoform analysis by RT-PCR, HDAC11 OE/KD","journal":"bioRxiv : the preprint server for biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay + metabolic labeling + mutagenesis + splicing readout, single lab preprint not yet peer-reviewed","pmids":["42124652"],"is_preprint":true},{"year":2025,"finding":"FGL2 (neutrophil-derived fibrinogen-like protein 2) interacts with HDAC11 in neutrophils, promoting histone H3 deacetylation and facilitating PAD4-mediated citrullination to drive NETs release and immunothrombosis in MASLD liver fibrosis.","method":"Co-immunoprecipitation of FGL2-HDAC11, histone H3 acetylation assays, PAD4 citrullination assays, FGL2 genetic disruption and NETs inhibition mouse models","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP with functional pathway assignment in single lab, abstract only; limited mechanistic detail available","pmids":["42107082"],"is_preprint":false}],"current_model":"HDAC11 is the sole class IV HDAC and functions primarily as a highly efficient lysine defatty-acylase (>10,000-fold more active than its deacetylase activity), with validated substrates including SHMT2 (regulating type I IFN signaling), gravin-α/AKAP12 (controlling thermogenesis via β-AR/UCP1 pathway), SF3B2 (modulating alternative splicing), BRAF K680 (suppressing kinase activity), TPI1 K69 (regulating protein stability in fibrosis), HSP90 K754 (controlling chemoresistance), and Parkin K76 (regulating mitophagy); it also deacetylates histones at specific gene promoters (IL-10, CCL2, PAI-1, LKB1, Nos2, C/EBPβ, tight junction proteins, cccDNA-bound histones) through chromatin-associated complexes involving HDAC6, BRD2, STAT3, KLF4, E4BP4, ERG, and the NuRD(MTA3) complex, collectively placing HDAC11 as a multifunctional epigenetic and acylation eraser enzyme that regulates immune tolerance, thermogenesis, T-cell effector function, muscle metabolism, DNA replication licensing, and viral restriction."},"narrative":{"mechanistic_narrative":"HDAC11 is the sole class IV histone deacetylase, an enzyme whose dominant biochemical activity is highly efficient lysine defatty-acylation (>10,000-fold more active than its canonical deacetylase function) and which acts as a multifunctional eraser of lysine acylation on both metabolic/signaling proteins and chromatin [PMID:11948178, PMID:30819897]. Through its catalytic activity it removes fatty-acyl and acetyl marks from a growing set of non-histone substrates with distinct functional consequences: defatty-acylation of SHMT2 suppresses type I IFN receptor levels and signaling [PMID:30819897], demyristoylation of gravin-α/AKAP12 restrains β-adrenergic/UCP1-driven thermogenesis [PMID:37607030], deacetylation of BRAF K680 suppresses kinase activity and proliferation [PMID:41273269], deacetylation of TPI1 K69 stabilizes the protein against ubiquitination to promote myofibroblast differentiation [PMID:41112094], and deacetylation of Parkin K76 promotes its degradation to impair mitophagy [PMID:41997918]. In parallel, HDAC11 functions as a chromatin-associated transcriptional repressor, being recruited to specific gene promoters where it lowers histone acetylation — repressing IL-10 in antigen-presenting cells [PMID:19011628], Eomes/Tbet to restrain T-cell effector function [PMID:28550044], Nos2 via STAT3 scaffolding [PMID:36087429], and the myogenic program in a catalytic-activity-dependent manner [PMID:28927261]. It carries out these promoter functions within or alongside protein complexes including HDAC6 [PMID:11948178, PMID:24747960], BRD2 [PMID:30089714], and the NuRD(MTA3) complex through its N-terminal region [PMID:41547814], and its abundance is controlled by ubiquitin-dependent turnover regulated by USP25 and March1 [PMID:31746627, PMID:34385821]. Collectively, HDAC11 links lysine acylation/deacylation chemistry to immune tolerance, thermogenesis and metabolism, fibrosis, and viral and transcriptional control.","teleology":[{"year":2002,"claim":"Established HDAC11 as a catalytically active, complex-forming deacetylase, defining the founding biochemical identity of the enzyme.","evidence":"In vitro deacetylase assay with trapoxin inhibition and Co-IP with HDAC6, nuclear localization by epitope tagging","pmids":["11948178"],"confidence":"High","gaps":["Physiological substrates not identified","Functional consequence of HDAC6 association unresolved"]},{"year":2008,"claim":"Showed HDAC11 is a promoter-associated transcriptional repressor with an immune function, repressing IL-10 to shape APC inflammatory phenotype and immune tolerance.","evidence":"Reciprocal overexpression/siRNA in APCs with ChIP at the IL-10 promoter and T-cell activation readouts","pmids":["19011628"],"confidence":"High","gaps":["Whether repression depends on direct histone deacetylation at this locus not isolated from complex effects","Recruitment mechanism to IL-10 promoter unknown"]},{"year":2010,"claim":"Extended HDAC11 function to DNA replication licensing by linking it to the Cdt1/Geminin axis and re-replication control.","evidence":"Co-IP of HDAC11 with Cdt1/Geminin, ChIP at origins, chromatin decondensation and re-replication assays","pmids":["20980834"],"confidence":"Medium","gaps":["Catalytic requirement for re-replication suppression not demonstrated","Single lab without in vivo confirmation"]},{"year":2017,"claim":"Demonstrated catalytic-activity-dependent transcriptional repression across tissues — of myogenic genes, of T-cell effector transcription factors Eomes/Tbet, and of CCL2 — cementing HDAC11 as a context-specific epigenetic repressor with immune and developmental roles.","evidence":"Active-site mutant in C2C12 myoblasts with promoter ChIP; KO and transgenic mice with ChIP at Eomes/Tbet and CCL2 promoters; EAE model","pmids":["28927261","28550044","30456376"],"confidence":"High","gaps":["Direct histone substrate versus non-histone substrate contributions not separated","Mechanism of promoter recruitment differs across loci and is not unified"]},{"year":2018,"claim":"Connected HDAC11 to systemic metabolism, showing its catalytic activity suppresses the thermogenic/BAT program via BRD2 and that its loss protects against diet-induced obesity.","evidence":"KO mice with metabolic phenotyping, Co-IP establishing HDAC11-BRD2 interaction, UCP1 and AMPK pathway readouts","pmids":["30089714","29958910"],"confidence":"High","gaps":["Molecular substrate of HDAC11 in the thermogenic program not yet identified at this stage","Role of BRD2 interaction in catalysis unresolved"]},{"year":2019,"claim":"Reframed HDAC11 enzymology by establishing lysine defatty-acylation as its dominant activity and identifying SHMT2 as a physiological substrate that controls type I IFN signaling.","evidence":"In vitro kinetic comparison of deacylase vs deacetylase activity, SILAC proteomics substrate ID, HDAC11 depletion in cells and mice with IFN readouts","pmids":["30819897"],"confidence":"High","gaps":["Generality of defatty-acylation across the prior promoter functions not addressed","Full substrate repertoire unknown"]},{"year":2019,"claim":"Showed HDAC11 protein levels are set by ubiquitin-dependent turnover, with USP25 stabilizing HDAC11 and smoke-induced USP25 loss reducing HDAC11 to alter antibacterial defense.","evidence":"Co-IP of USP25 with HDAC11, CSE treatment and protein stability assays, bacterial load readout","pmids":["31746627"],"confidence":"Medium","gaps":["Ubiquitination site on HDAC11 not mapped","Single lab Co-IP-based mechanism"]},{"year":2021,"claim":"Defined March1 as an E3 ligase degrading HDAC11 and placed HDAC11 in a KLF4 complex repressing OX40L, integrating turnover control with transcriptional output.","evidence":"Co-IP, ubiquitination assay, KLF4-HDAC11 complex detection and OX40L luciferase promoter assay","pmids":["34385821"],"confidence":"Medium","gaps":["Ubiquitination site not defined","Direct versus indirect repression of OX40L not separated"]},{"year":2022,"claim":"Provided a mechanistic model for promoter targeting, showing STAT3 scaffolds HDAC11 to the Nos2 promoter to repress iNOS and antifungal killing.","evidence":"ChIP at Nos2, Co-IP with STAT3, KO mice, pharmacological inhibition (FT895), fungal killing assays","pmids":["36087429"],"confidence":"High","gaps":["Whether STAT3 scaffolding generalizes to other repressed promoters unknown"]},{"year":2023,"claim":"Identified the molecular substrate underlying HDAC11's metabolic role, demonstrating demyristoylation of gravin-α/AKAP12 gates β-AR/UCP1 thermogenic signaling, and uncovered HSP90 K754 debutyrylation linking HDAC11 acyl-eraser activity to chemoresistance.","evidence":"Adipocyte-specific KO, FT895 inhibition, gravin-α myristoylation and PKA assays; butyrylome MS, in vitro deacylase assay and SDCBP-HDAC11 Co-IP for HSP90","pmids":["37607030","37460462"],"confidence":"High","gaps":["Whether other acyl marks (butyrylation) are broadly erased by HDAC11 in vivo not established"]},{"year":2025,"claim":"Expanded the non-histone substrate repertoire through proteomics-based mutant trapping and site-specific assays, identifying BRAF K680, TPI1 K69, and Parkin K76 as substrates that couple HDAC11 to proliferation, fibrosis, and mitophagy.","evidence":"Proteomics mutant trapping, in vitro site-specific deacetylation, kinase/ubiquitination/mitophagy assays, KO mice and FT895 in fibrosis models","pmids":["41273269","41112094","41997918"],"confidence":"Medium","gaps":["Most of 64 putative substrates remain unvalidated","Single-lab validations per substrate"]},{"year":2026,"claim":"Showed HDAC11 acts through the NuRD(MTA3) complex via its N-terminal region to repress TGFB1 and restrain HCC metastasis, defining a stable chromatin-modifying complex partner.","evidence":"MS, Co-IP and GST pull-down mapping the N-terminal interaction with MTA3, transcriptomics, in vivo metastasis rescue by TGFB1 knockdown","pmids":["41547814"],"confidence":"Medium","gaps":["Catalytic requirement within the NuRD complex not isolated","Single lab"]},{"year":null,"claim":"It remains unresolved how HDAC11 selects between histone deacetylation and non-histone defatty-acylation in a given cellular context, and what determines its recruitment to specific promoters versus cytoplasmic/mitochondrial substrates.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking acyl-substrate preference to subcellular targeting","Recruitment determinants across diverse promoters not generalized","SF3B2/splicing role rests on a preprint"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,23,26,27,28,22]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,8,21,9]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,1,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[1,8,21]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,8,21]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[11,12,17,23]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,8,9,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,23,26]}],"complexes":["NuRD(MTA3) complex"],"partners":["HDAC6","BRD2","STAT3","KLF4","E4BP4","ERG","MTA3","VDR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96DB2","full_name":"Histone deacetylase 11","aliases":[],"length_aa":347,"mass_kda":39.2,"function":"Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. 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Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/40065721","citation_count":1,"is_preprint":false},{"pmid":"36281860","id":"PMC_36281860","title":"WITHDRAWN: Overexpression of NR4A2 Alleviates Renal and Myocardial Injury in Diabetic Nephropathy in Rats Through the HDAC11/ SPRY1 Pathway.","date":"2025","source":"Endocrine, metabolic & immune disorders drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/36281860","citation_count":1,"is_preprint":false},{"pmid":"40220154","id":"PMC_40220154","title":"HDAC11 deficiency regulates age-related muscle decline and sarcopenia.","date":"2025","source":"GeroScience","url":"https://pubmed.ncbi.nlm.nih.gov/40220154","citation_count":0,"is_preprint":false},{"pmid":"41273269","id":"PMC_41273269","title":"HDAC11 Deacetylates BRAF to Regulate Kinase Activity and Cell Proliferation.","date":"2025","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/41273269","citation_count":0,"is_preprint":false},{"pmid":"37034582","id":"PMC_37034582","title":"HDAC11 inhibition triggers bimodal thermogenic pathways to circumvent adipocyte catecholamine resistance.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37034582","citation_count":0,"is_preprint":false},{"pmid":"40386380","id":"PMC_40386380","title":"HDAC11 promotes renal fibrosis by induing partial epithelial-mesenchymal transition and G2/M phase arrest in renal epithelial cells.","date":"2025","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/40386380","citation_count":0,"is_preprint":false},{"pmid":"41547814","id":"PMC_41547814","title":"HDAC11 interacts with the NuRD (MTA3) complex to transcriptionally suppress TGFβ1 expression and inhibit hepatocellular carcinoma metastasis.","date":"2026","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/41547814","citation_count":0,"is_preprint":false},{"pmid":"37245910","id":"PMC_37245910","title":"Identification of potential HDAC11 deacylase substrates by affinity pulldown MS.","date":"2023","source":"Methods in enzymology","url":"https://pubmed.ncbi.nlm.nih.gov/37245910","citation_count":0,"is_preprint":false},{"pmid":"41997918","id":"PMC_41997918","title":"Hdac11 promotes idiopathic pulmonary fibrosis through macrophage M2-type polarization and myofibroblast accumulation by inhibiting Parkin-dependent mitophagy.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41997918","citation_count":0,"is_preprint":false},{"pmid":"42107082","id":"PMC_42107082","title":"FGL2-HDAC11 Drives Immunothrombosis via NETs-Mediated Endothelial Capillarization in MASLD Fibrosis.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/42107082","citation_count":0,"is_preprint":false},{"pmid":"42124652","id":"PMC_42124652","title":"HDAC11 Regulates RNA Splicing via De-Fatty Acylation of SF3B2.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42124652","citation_count":0,"is_preprint":false},{"pmid":"41407152","id":"PMC_41407152","title":"HDAC11 deficiency improves muscle phenotype in a Duchenne muscular dystrophy murine model by reducing inflammation and fibrosis.","date":"2025","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41407152","citation_count":0,"is_preprint":false},{"pmid":"42126774","id":"PMC_42126774","title":"Super-enhancer-associated lncRNA HDAC11-AS1 aggravates hepatocellular carcinoma progression by modulating HDAC11 and NUP210 expression via promoting super-enhancer activity.","date":"2026","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/42126774","citation_count":0,"is_preprint":false},{"pmid":"41787751","id":"PMC_41787751","title":"Discovery of a Hydroxamic Acid-Based HDAC11 Isoform-Selective Inhibitor with Oral Anti-AML Potency.","date":"2026","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41787751","citation_count":0,"is_preprint":false},{"pmid":"37387751","id":"PMC_37387751","title":"Retracted: Long Noncoding RNA TFAP2A-AS1 Suppressed Hepatitis B Virus Replication by Modulating miR-933/HDAC11.","date":"2023","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/37387751","citation_count":0,"is_preprint":false},{"pmid":"41668160","id":"PMC_41668160","title":"Epigenetic regulation by HDAC11-driven STAT3 activation promotes pro-inflammatory cytokine production and endothelial dysfunction upon bacterial infection in diabetes.","date":"2026","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/41668160","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.17.683079","title":"Inhibition of CGRP receptor ameliorates AD pathology by reprogramming lipid metabolism through HDAC11/LXRβ/ABCA1 signaling","date":"2025-10-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.17.683079","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.07.606975","title":"Research on the Mechanism of Lphn1 Knockout in Inhibiting Colorectal 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Co-immunoprecipitation, nuclear localization by epitope-tag imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzymatic assay with inhibitor validation plus Co-IP, founding paper replicated by many subsequent studies\",\n      \"pmids\": [\"11948178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HDAC11 negatively regulates IL-10 gene expression in antigen-presenting cells (APCs) by associating with the IL-10 promoter chromatin, thereby promoting inflammatory APC phenotype and suppressing immune tolerance.\",\n      \"method\": \"HDAC11 overexpression and siRNA knockdown in APCs, IL-10 expression assays, chromatin immunoprecipitation (ChIP) at the IL-10 promoter, T cell activation assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function with ChIP validation, replicated across multiple subsequent studies\",\n      \"pmids\": [\"19011628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HDAC6 (a cytoplasmic protein) and HDAC11 (a nuclear protein) are both recruited to the IL-10 gene promoter in APCs, but with divergent transcriptional effects: HDAC11 represses IL-10 while HDAC6 acts as a transcriptional activator; the two HDACs physically associate.\",\n      \"method\": \"ChIP showing co-recruitment of HDAC6 and HDAC11 to the IL-10 promoter, co-immunoprecipitation, siRNA knockdown of each HDAC\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and ChIP in single lab with two orthogonal methods\",\n      \"pmids\": [\"24747960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HDAC11 functions as an efficient lysine defatty-acylase (>10,000-fold more efficient than its deacetylase activity) and defatty-acylates SHMT2 at a specific lysine residue; this modification does not affect SHMT2 enzymatic activity but regulates type I IFN receptor ubiquitination and cell-surface levels, thereby suppressing type I IFN signaling in cells and mice.\",\n      \"method\": \"In vitro biochemical deacylase assay, SILAC proteomics for substrate identification, biochemical validation of SHMT2 as substrate, HDAC11 depletion in cells and mice with IFN signaling readouts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with kinetic comparison, proteomics-based substrate identification, and in vivo validation in one rigorous study\",\n      \"pmids\": [\"30819897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HDAC11 represses HBV cccDNA transcription by deacetylating cccDNA-bound histone H3, specifically reducing H3K9ac and H3K27ac marks on cccDNA; this restricts HBV replication without affecting cccDNA production.\",\n      \"method\": \"ChIP assay on cccDNA-bound histones, HDAC11 overexpression/knockdown in HBV-transfected cells, HBV replication assays\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional replication readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"31600533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HDAC11 binds Cdt1 (and does so more efficiently in the presence of Geminin) at replication origins during S-phase, inhibiting Cdt1-induced chromatin decondensation and MCM loading, thereby suppressing re-replication; this is counteracted by HBO1 HAT activity in G1.\",\n      \"method\": \"Co-immunoprecipitation of HDAC11 with Cdt1/Geminin, ChIP at replication origins, chromatin decondensation assays, re-replication assays\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and ChIP with functional re-replication readout, single lab\",\n      \"pmids\": [\"20980834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HDAC11 regulates OX40 ligand (OX40L) expression in Hodgkin lymphoma cells; siRNA-mediated depletion of HDAC11 upregulates OX40L surface expression, increases TNF-α and IL-17 production, and induces apoptosis.\",\n      \"method\": \"siRNA knockdown of HDAC11, flow cytometry for OX40L surface expression, cytokine measurement in supernatants\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"21239696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HDAC11 binds the promoter region of the PAI-1 gene in a gender-specific manner (regulated by male hormone/testosterone/dihydrotestosterone); I/R injury or LPS causes HDAC11 to dissociate from the PAI-1 promoter, increasing local histone H3 acetylation and PAI-1 expression.\",\n      \"method\": \"ChIP assay showing HDAC11 binding to PAI-1 promoter, orchiectomy/DHT experiments, HDAC11 gene silencing with PAI-1 expression readout\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with loss-of-function validation, single lab\",\n      \"pmids\": [\"23657855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC11 is present at the Eomes and Tbet gene promoters in resting T cells (shown by ChIP) and dissociates upon T-cell activation; loss of HDAC11 increases Eomes and Tbet expression, enhancing T cell effector functions, cytokine production, and proliferation, while HDAC11 overexpression suppresses these genes.\",\n      \"method\": \"ChIP at Eomes/Tbet promoters, HDAC11 KO and transgenic overexpression mouse models, cytokine and transcription factor expression assays, in vivo GVHD model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP with KO and OE mouse models, multiple orthogonal readouts replicated in vivo\",\n      \"pmids\": [\"28550044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC11 suppresses myoblast differentiation in a catalytic-activity-dependent manner; wild-type HDAC11 inhibits MyoD-dependent transcription of MEF2C and Myogenin by reducing histone acetylation near E-boxes at their promoters, whereas a catalytically inactive mutant (H142/143A) does not impede differentiation.\",\n      \"method\": \"Ectopic expression of WT and catalytically inactive HDAC11 mutant in C2C12 myoblasts, MyoD-dependent promoter activity assays (luciferase), histone acetylation ChIP at MEF2C and MYOG promoters\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis paired with promoter activity and ChIP assays in single study\",\n      \"pmids\": [\"28927261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC11 controls CCL2 (MCP-1) gene expression by enabling binding of the transcription factor PU.1 to the CCL2 promoter; loss of HDAC11 reduces CCL2-driven monocyte/DC infiltration into the CNS and ameliorates EAE severity.\",\n      \"method\": \"HDAC11 KO mouse model, EAE (MS model), ChIP/promoter analysis of CCL2, immune cell infiltration analysis\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with ChIP-based promoter mechanism, single lab\",\n      \"pmids\": [\"30456376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HDAC11 catalytic activity suppresses the brown adipose tissue (BAT) transcriptional program through physical association with BRD2, a bromodomain acetyl-histone-binding protein; HDAC11 deletion in mice stimulates BAT formation, beiging of WAT, and enhances thermogenic potential.\",\n      \"method\": \"HDAC11 KO mouse model, ex vivo and cell-based assays showing HDAC11-BRD2 physical interaction (Co-IP), β-adrenergic receptor signaling assays, UCP1 expression readouts\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with Co-IP establishing BRD2 interaction plus multiple cellular and in vivo readouts, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30089714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HDAC11 deficiency in mice confers resistance to high-fat diet-induced obesity; mechanistically, HDAC11 depletion boosts UCP1 expression and thermogenic capacity in BAT and activates the adiponectin-AdipoR-AMPK pathway in the liver.\",\n      \"method\": \"HDAC11 KO mouse model on HFD, metabolic phenotyping, UCP1 expression assays, AMPK pathway analysis\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with metabolic phenotyping, single lab\",\n      \"pmids\": [\"29958910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HDAC11 forms a complex with E4BP4 transcription factor in cardiac CD4+ T cells and restricts E4BP4 binding to the IL-13 promoter, thereby repressing IL-13 transcription; reconstitution of HDAC11 in myocarditis T cells reduced IL-13 expression.\",\n      \"method\": \"Co-immunoprecipitation of HDAC11–E4BP4 complex, HDAC11 reconstitution and inhibition in patient-derived CD4+ T cells, IL-13 expression assays\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and gain/loss-of-function in primary cells, single lab\",\n      \"pmids\": [\"30063898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP25 deubiquitinates HDAC11, stabilizing it; cigarette smoke extract (CSE) promotes USP25 ubiquitination and degradation, thereby reducing HDAC11 protein levels (without affecting HDAC11 transcript), increasing bacterial load; USP25–HDAC11 interaction demonstrated by Co-IP.\",\n      \"method\": \"Co-immunoprecipitation of USP25 and HDAC11, CSE treatment with protein stability assays, siRNA/OE of USP25, bacterial load assay\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with functional validation, single lab\",\n      \"pmids\": [\"31746627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HDAC11 inhibition in mouse oocytes (by specific inhibitor JB3-22) increases α-tubulin acetylation and H4K16 acetylation, disrupts spindle organization, causes chromosome misalignment, impairs kinetochore-microtubule attachment and spindle assembly checkpoint, thereby blocking meiotic progression.\",\n      \"method\": \"HDAC11-specific inhibitor (JB3-22) treatment of mouse oocytes, immunofluorescence for spindle/chromosome/kinetochore markers, acetylation level measurement\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with multiple orthogonal cellular readouts, single lab\",\n      \"pmids\": [\"31910069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HDAC11 depletion in HCC increases histone acetylation at the LKB1 promoter, activating LKB1 transcription and thus the AMPK signaling pathway, which inhibits glycolysis and suppresses cancer stemness; conditional HDAC11 KO mice showed reduced hepatocellular tumorigenesis.\",\n      \"method\": \"Conditional KO mouse model, ChIP at LKB1 promoter, AMPK/glycolysis pathway analysis, stemness assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with ChIP mechanism, single lab\",\n      \"pmids\": [\"33602787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HDAC11 is localized in skeletal muscle mitochondria; its genetic deficiency enhances mitochondrial fatty acid β-oxidation through activating the AMPK-acetyl-CoA carboxylase pathway, reduces acylcarnitine levels, increases oxidative myofibers, and improves muscle fatigue resistance and strength.\",\n      \"method\": \"HDAC11 KO mouse model, mitochondrial fractionation/localization by imaging, AMPK-ACC pathway assays, metabolomics (acylcarnitines), fiber-type analysis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with subcellular fractionation and multiple metabolic/functional readouts, single lab\",\n      \"pmids\": [\"32563202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HDAC11 forms a complex with ERG and decreases ERG acetylation levels; HDAC11 knockdown mitigates TNF-α-induced pyroptosis via suppression of both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways in vascular endothelial cells.\",\n      \"method\": \"Co-immunoprecipitation of HDAC11 with ERG, acetylation assays of ERG, siRNA knockdown of HDAC11/GSDME in HUVECs, pyroptosis markers (caspase-1, caspase-3, GSDMD, GSDME, LDH, PI staining)\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and siRNA KD with multiple pyroptosis readouts, single lab\",\n      \"pmids\": [\"35279683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HDAC11 is recruited to the C/EBPβ gene promoter in MDSCs (shown by ChIP); loss of HDAC11 upregulates C/EBPβ, leading to elevated arginase activity and NO production that enhance MDSC suppressive function.\",\n      \"method\": \"ChIP showing HDAC11 at C/EBPβ promoter in WT MDSCs, HDAC11 KO mouse-derived MDSCs, arginase activity and iNOS/NO assays\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with KO mouse functional readouts, single lab\",\n      \"pmids\": [\"33866588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"March1 (an E3 ubiquitin ligase) directly ubiquitinates HDAC11, promoting its degradation; HDAC11 forms a complex with transcription factor KLF4 to repress OX40L gene promoter activity; loss of HDAC11 (via March1-induced degradation) de-represses OX40L expression.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, luciferase promoter assay, ubiquitination assay, KLF4–HDAC11 complex detection\",\n      \"journal\": \"Journal of asthma and allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with promoter luciferase, single lab\",\n      \"pmids\": [\"34385821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC11 negatively regulates Nos2 (iNOS) expression in macrophages through its association with STAT3 (which acts as a scaffold protein anchoring HDAC11 to the Nos2 promoter); HDAC11 deficiency increases H3/H4 acetylation at the Nos2 promoter, boosting iNOS and NO-mediated antifungal killing.\",\n      \"method\": \"ChIP at Nos2 promoter, Co-IP of HDAC11 with STAT3, HDAC11 KO mouse model, fungal killing assays, HDAC11 inhibitor (FT895) in mouse and human cells\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP + Co-IP + KO mouse + pharmacological inhibition with in vivo and in vitro validation in single study\",\n      \"pmids\": [\"36087429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC11 acts as the eraser of lysine butyrylation (Kbu) on HSP90 at K754; KAT8 is the writer of this modification; SDCBP increases Kbu on HSP90 by competitively binding to HDAC11, preventing its eraser activity, leading to HSP90 overexpression and chemoresistance.\",\n      \"method\": \"Butyrylome profiling MS, gain/loss-of-function experiments, in vitro deacylase assays identifying HDAC11 as Kbu eraser for HSP90 K754, Co-IP of SDCBP–HDAC11\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS substrate identification plus in vitro enzymatic assay and Co-IP, single lab\",\n      \"pmids\": [\"37460462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC11 demyristoylates gravin-α (AKAP12); HDAC11 inhibition preserves gravin-α myristoylation, enabling β-adrenergic receptor signaling that induces UCP1 expression via a biphasic mechanism: an acute PKA-independent post-transcriptional response and a delayed PKA-dependent transcriptional response; adipocyte-specific HDAC11 deletion robustly induces UCP1 in adipose tissue and elevates body temperature.\",\n      \"method\": \"Adipocyte-specific HDAC11 KO mice, HDAC11-selective inhibitor FT895 in vivo and ex vivo (human AT), gravin-α myristoylation assays, UCP1 expression (protein/mRNA), PKA activity assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — tissue-specific KO + pharmacological inhibition + substrate myristoylation assays + multiple mechanistic readouts in one study\",\n      \"pmids\": [\"37607030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC11 is synaptic-enriched (not exclusively nuclear/cytoplasmic as previously reported) in brain tissue; in HDAC11 KO mice, loss of HDAC11 selectively decreases Fez1 expression in the hippocampus in an age-dependent and brain-region-specific manner.\",\n      \"method\": \"Subcellular fractionation showing synaptic enrichment, HDAC11 KO mouse brain analysis, Fez1 expression in cortical/cerebellar/hippocampal regions\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation-based localization and KO mouse with region-specific readout, single lab\",\n      \"pmids\": [\"28928414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"VDR (vitamin D receptor) forms a complex with HDAC11 in intestinal epithelial cells under VitD-sufficient conditions; in VitD-deficient conditions, HDAC11 binding to tight junction protein promoters increases, repressing their transcription and impairing barrier function; calcitriol abolishes this repressive HDAC11 promoter binding.\",\n      \"method\": \"Co-immunoprecipitation of VDR–HDAC11, ChIP at tight junction protein promoters, calcitriol treatment, epithelial barrier function assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP with functional readout, single lab\",\n      \"pmids\": [\"28938596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC11 deacetylates BRAF at K680, suppressing BRAF kinase activity and reducing cell proliferation; proteomics-based mutant trapping identified BRAF among 64 putative HDAC11 substrates.\",\n      \"method\": \"Proteomics mutant trapping to identify substrates, biochemical deacetylation assay of BRAF K680, kinase activity assay, cell proliferation assay\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — proteomics substrate identification plus in vitro enzymatic and kinase activity validation, single lab\",\n      \"pmids\": [\"41273269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC11 deacetylates TPI1 (triosephosphate isomerase 1) at K69, stabilizing TPI1 by attenuating K48-linked polyubiquitination; this stabilization promotes fibroblast-to-myofibroblast differentiation, proliferation, and migration in pulmonary fibrosis; TGF-β1 enhances this HDAC11-mediated deacetylation.\",\n      \"method\": \"In vitro deacetylation assay, site-specific mutagenesis (K69), ubiquitination assay, TGF-β1 stimulation in fibroblasts, KO mice and HDAC11 inhibitor (FT895) in bleomycin fibrosis model\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic + mutagenesis + ubiquitination assay + in vivo model, single lab\",\n      \"pmids\": [\"41112094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC11 deacetylates Parkin at K76, promoting Parkin ubiquitination and degradation; this impairs mitophagy and drives pro-fibrotic M2 macrophage polarization and macrophage-myofibroblast transition in idiopathic pulmonary fibrosis; adoptive transfer of HDAC11-deficient macrophages attenuates fibrosis.\",\n      \"method\": \"Site-specific deacetylation assay (Parkin K76), ubiquitination assay, HDAC11 KO mouse and macrophage adoptive transfer, mitophagy assays, fibrosis histology\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic assay at specific site + KO mouse adoptive transfer, single lab\",\n      \"pmids\": [\"41997918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"HDAC11 interacts with the NuRD (MTA3) complex through its N-terminal region; this complex transcriptionally represses TGFB1, thereby inhibiting HCC metastasis; HDAC11 silencing increases TGFB1 expression and metastatic potential, which is reversed by concurrent TGFB1 knockdown.\",\n      \"method\": \"Mass spectrometry identifying HDAC11-NuRD(MTA3) interaction, Co-IP and GST pull-down of HDAC11 N-terminal region with MTA3, transcriptomic analysis, in vitro and in vivo metastasis assays\",\n      \"journal\": \"Clinical epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS + Co-IP + GST pull-down + in vivo rescue experiment, single lab\",\n      \"pmids\": [\"41547814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"HDAC11 regulates RNA splicing via de-fatty acylation (de-myristoylation) of the spliceosomal protein SF3B2 at K10; a de-myristoylation mimetic mutant (K10R) exhibits altered pre-mRNA binding and promotes alternative splicing toward the AR-v7 variant in HCC cells in a cell-type-specific manner.\",\n      \"method\": \"Metabolic labeling, mass spectrometry, click chemistry, in vitro deacylase assay establishing SF3B2 K10 as direct HDAC11 substrate, SF3B2 K10R mutagenesis, AR splicing isoform analysis by RT-PCR, HDAC11 OE/KD\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay + metabolic labeling + mutagenesis + splicing readout, single lab preprint not yet peer-reviewed\",\n      \"pmids\": [\"42124652\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FGL2 (neutrophil-derived fibrinogen-like protein 2) interacts with HDAC11 in neutrophils, promoting histone H3 deacetylation and facilitating PAD4-mediated citrullination to drive NETs release and immunothrombosis in MASLD liver fibrosis.\",\n      \"method\": \"Co-immunoprecipitation of FGL2-HDAC11, histone H3 acetylation assays, PAD4 citrullination assays, FGL2 genetic disruption and NETs inhibition mouse models\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP with functional pathway assignment in single lab, abstract only; limited mechanistic detail available\",\n      \"pmids\": [\"42107082\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HDAC11 is the sole class IV HDAC and functions primarily as a highly efficient lysine defatty-acylase (>10,000-fold more active than its deacetylase activity), with validated substrates including SHMT2 (regulating type I IFN signaling), gravin-α/AKAP12 (controlling thermogenesis via β-AR/UCP1 pathway), SF3B2 (modulating alternative splicing), BRAF K680 (suppressing kinase activity), TPI1 K69 (regulating protein stability in fibrosis), HSP90 K754 (controlling chemoresistance), and Parkin K76 (regulating mitophagy); it also deacetylates histones at specific gene promoters (IL-10, CCL2, PAI-1, LKB1, Nos2, C/EBPβ, tight junction proteins, cccDNA-bound histones) through chromatin-associated complexes involving HDAC6, BRD2, STAT3, KLF4, E4BP4, ERG, and the NuRD(MTA3) complex, collectively placing HDAC11 as a multifunctional epigenetic and acylation eraser enzyme that regulates immune tolerance, thermogenesis, T-cell effector function, muscle metabolism, DNA replication licensing, and viral restriction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HDAC11 is the sole class IV histone deacetylase, an enzyme whose dominant biochemical activity is highly efficient lysine defatty-acylation (>10,000-fold more active than its canonical deacetylase function) and which acts as a multifunctional eraser of lysine acylation on both metabolic/signaling proteins and chromatin [#0, #3]. Through its catalytic activity it removes fatty-acyl and acetyl marks from a growing set of non-histone substrates with distinct functional consequences: defatty-acylation of SHMT2 suppresses type I IFN receptor levels and signaling [#3], demyristoylation of gravin-\\u03b1/AKAP12 restrains \\u03b2-adrenergic/UCP1-driven thermogenesis [#23], deacetylation of BRAF K680 suppresses kinase activity and proliferation [#26], deacetylation of TPI1 K69 stabilizes the protein against ubiquitination to promote myofibroblast differentiation [#27], and deacetylation of Parkin K76 promotes its degradation to impair mitophagy [#28]. In parallel, HDAC11 functions as a chromatin-associated transcriptional repressor, being recruited to specific gene promoters where it lowers histone acetylation \\u2014 repressing IL-10 in antigen-presenting cells [#1], Eomes/Tbet to restrain T-cell effector function [#8], Nos2 via STAT3 scaffolding [#21], and the myogenic program in a catalytic-activity-dependent manner [#9]. It carries out these promoter functions within or alongside protein complexes including HDAC6 [#0, #2], BRD2 [#11], and the NuRD(MTA3) complex through its N-terminal region [#29], and its abundance is controlled by ubiquitin-dependent turnover regulated by USP25 and March1 [#14, #20]. Collectively, HDAC11 links lysine acylation/deacylation chemistry to immune tolerance, thermogenesis and metabolism, fibrosis, and viral and transcriptional control.\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established HDAC11 as a catalytically active, complex-forming deacetylase, defining the founding biochemical identity of the enzyme.\",\n      \"evidence\": \"In vitro deacetylase assay with trapoxin inhibition and Co-IP with HDAC6, nuclear localization by epitope tagging\",\n      \"pmids\": [\"11948178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates not identified\", \"Functional consequence of HDAC6 association unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed HDAC11 is a promoter-associated transcriptional repressor with an immune function, repressing IL-10 to shape APC inflammatory phenotype and immune tolerance.\",\n      \"evidence\": \"Reciprocal overexpression/siRNA in APCs with ChIP at the IL-10 promoter and T-cell activation readouts\",\n      \"pmids\": [\"19011628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether repression depends on direct histone deacetylation at this locus not isolated from complex effects\", \"Recruitment mechanism to IL-10 promoter unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended HDAC11 function to DNA replication licensing by linking it to the Cdt1/Geminin axis and re-replication control.\",\n      \"evidence\": \"Co-IP of HDAC11 with Cdt1/Geminin, ChIP at origins, chromatin decondensation and re-replication assays\",\n      \"pmids\": [\"20980834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic requirement for re-replication suppression not demonstrated\", \"Single lab without in vivo confirmation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated catalytic-activity-dependent transcriptional repression across tissues \\u2014 of myogenic genes, of T-cell effector transcription factors Eomes/Tbet, and of CCL2 \\u2014 cementing HDAC11 as a context-specific epigenetic repressor with immune and developmental roles.\",\n      \"evidence\": \"Active-site mutant in C2C12 myoblasts with promoter ChIP; KO and transgenic mice with ChIP at Eomes/Tbet and CCL2 promoters; EAE model\",\n      \"pmids\": [\"28927261\", \"28550044\", \"30456376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct histone substrate versus non-histone substrate contributions not separated\", \"Mechanism of promoter recruitment differs across loci and is not unified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected HDAC11 to systemic metabolism, showing its catalytic activity suppresses the thermogenic/BAT program via BRD2 and that its loss protects against diet-induced obesity.\",\n      \"evidence\": \"KO mice with metabolic phenotyping, Co-IP establishing HDAC11-BRD2 interaction, UCP1 and AMPK pathway readouts\",\n      \"pmids\": [\"30089714\", \"29958910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular substrate of HDAC11 in the thermogenic program not yet identified at this stage\", \"Role of BRD2 interaction in catalysis unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reframed HDAC11 enzymology by establishing lysine defatty-acylation as its dominant activity and identifying SHMT2 as a physiological substrate that controls type I IFN signaling.\",\n      \"evidence\": \"In vitro kinetic comparison of deacylase vs deacetylase activity, SILAC proteomics substrate ID, HDAC11 depletion in cells and mice with IFN readouts\",\n      \"pmids\": [\"30819897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of defatty-acylation across the prior promoter functions not addressed\", \"Full substrate repertoire unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed HDAC11 protein levels are set by ubiquitin-dependent turnover, with USP25 stabilizing HDAC11 and smoke-induced USP25 loss reducing HDAC11 to alter antibacterial defense.\",\n      \"evidence\": \"Co-IP of USP25 with HDAC11, CSE treatment and protein stability assays, bacterial load readout\",\n      \"pmids\": [\"31746627\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site on HDAC11 not mapped\", \"Single lab Co-IP-based mechanism\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined March1 as an E3 ligase degrading HDAC11 and placed HDAC11 in a KLF4 complex repressing OX40L, integrating turnover control with transcriptional output.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, KLF4-HDAC11 complex detection and OX40L luciferase promoter assay\",\n      \"pmids\": [\"34385821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site not defined\", \"Direct versus indirect repression of OX40L not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided a mechanistic model for promoter targeting, showing STAT3 scaffolds HDAC11 to the Nos2 promoter to repress iNOS and antifungal killing.\",\n      \"evidence\": \"ChIP at Nos2, Co-IP with STAT3, KO mice, pharmacological inhibition (FT895), fungal killing assays\",\n      \"pmids\": [\"36087429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAT3 scaffolding generalizes to other repressed promoters unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified the molecular substrate underlying HDAC11's metabolic role, demonstrating demyristoylation of gravin-\\u03b1/AKAP12 gates \\u03b2-AR/UCP1 thermogenic signaling, and uncovered HSP90 K754 debutyrylation linking HDAC11 acyl-eraser activity to chemoresistance.\",\n      \"evidence\": \"Adipocyte-specific KO, FT895 inhibition, gravin-\\u03b1 myristoylation and PKA assays; butyrylome MS, in vitro deacylase assay and SDCBP-HDAC11 Co-IP for HSP90\",\n      \"pmids\": [\"37607030\", \"37460462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other acyl marks (butyrylation) are broadly erased by HDAC11 in vivo not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the non-histone substrate repertoire through proteomics-based mutant trapping and site-specific assays, identifying BRAF K680, TPI1 K69, and Parkin K76 as substrates that couple HDAC11 to proliferation, fibrosis, and mitophagy.\",\n      \"evidence\": \"Proteomics mutant trapping, in vitro site-specific deacetylation, kinase/ubiquitination/mitophagy assays, KO mice and FT895 in fibrosis models\",\n      \"pmids\": [\"41273269\", \"41112094\", \"41997918\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most of 64 putative substrates remain unvalidated\", \"Single-lab validations per substrate\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed HDAC11 acts through the NuRD(MTA3) complex via its N-terminal region to repress TGFB1 and restrain HCC metastasis, defining a stable chromatin-modifying complex partner.\",\n      \"evidence\": \"MS, Co-IP and GST pull-down mapping the N-terminal interaction with MTA3, transcriptomics, in vivo metastasis rescue by TGFB1 knockdown\",\n      \"pmids\": [\"41547814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic requirement within the NuRD complex not isolated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how HDAC11 selects between histone deacetylation and non-histone defatty-acylation in a given cellular context, and what determines its recruitment to specific promoters versus cytoplasmic/mitochondrial substrates.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking acyl-substrate preference to subcellular targeting\", \"Recruitment determinants across diverse promoters not generalized\", \"SF3B2/splicing role rests on a preprint\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 23, 26, 27, 28, 22]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 8, 21, 9]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [1, 8, 21]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 8, 21]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [11, 12, 17, 23]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 8, 9, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 23, 26]}\n    ],\n    \"complexes\": [\n      \"NuRD(MTA3) complex\"\n    ],\n    \"partners\": [\n      \"HDAC6\",\n      \"BRD2\",\n      \"STAT3\",\n      \"KLF4\",\n      \"E4BP4\",\n      \"ERG\",\n      \"MTA3\",\n      \"VDR\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}