HDAC6 deficiency exacerbates atherosclerosis via STAT3-K685 acetylation-mediated CD36/SR-A upregulation in macrophages.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:41444216", "kind": "science-record", "revision": 4, "content_hash": "sha256:9174d20ef4a0ea36c3cf2965ee8550e688cf6707608b0811c8ffc1a45acd43e1", "created_at": "2026-11-01T20:31:25Z", "updated_at": "2026-11-01T22:57:38Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "HDAC6 deficiency exacerbates atherosclerosis via STAT3-K685 acetylation-mediated CD36/SR-A upregulation in macrophages.", "doi": "10.1038/s41419-025-08344-y", "pmid": "41444216", "authors": ["Wenqing Wang", "Yue Jiang", "Xuan Pan", "Dong Chen", "Hui Yang", "Wang Pan", "Mingjie Pan", "Bin Wang"], "journal": "Cell death & disease", "year": 2025, "abstract": "Atherosclerosis (AS) is a prevalent chronic arterial disease characterized by excessive cholesterol accumulation in the arterial intima. While substantial progress has been made in elucidating its risk factors and pathogenesis, the upstream signaling molecules that drive the initiation and progression of AS remain poorly understood. Analysis of monocyte samples from the GSE23746 database revealed that Histone Deacetylase 6 (HDAC6) expression was significantly downregulated in patients with carotid atherosclerosis compared to healthy controls. In vitro experiments further demonstrated that HDAC6 deficiency markedly promotes foam cell formation in macrophages, a process dependent on its deacetylase activity. Mechanistically, HDAC6 interacts with signal transducer and activator of transcription 3 (STAT3) and regulates its acetylation at K685, a critical modification that facilitates macrophage foam cell formation. Specifically, the loss of HDAC6-mediated deacetylation leads to increased STAT3-K685 acetylation, which in turn upregulates the expression of CD36 and SRA, thereby enhancing cholesterol uptake in macrophages. Our findings establish HDAC6 as a protective regulator in atherosclerosis, which maintains lipid metabolic homeostasis by modulating the STAT3-CD36/SR-A axis. We also observed that systemic HDAC6 knockout exacerbated atherosclerotic progression in high-fat diet-fed ApoE⁻/⁻mice, accompanied by increased monocyte/macrophage infiltration into plaques. Collectively, this study establishes HDAC6 as a potential therapeutic target for atherosclerosis intervention.", "claims": [{"id": "claim-method", "statement": "The differentially expressed genes were calculated by Student's t test. To evaluate the association between the gene expression and survival, we categorized the samples into two group by median of individual gene expression. The P value of trend was generated by the Cox regression model. 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HDAC6−/− mice and ApoE−/− mice were bred to generate ApoE−/−/HDAC6−/− mice. DNAs", "E−/− (n = 14), and ApoE−/−/HDAC6−/− (n = 14) mice were fed with high-fat diet (HFD, containing 40%", "is included in figure legends. Cell cultures Murine macrophage cell line Raw264.7 cells (TIB-71;", "to generate ApoE−/−/HDAC6−/− mice. DNAs from mouse tails were extracted by the One Step Mouse G"], "order_basis": "paper_text_order:2158", "id": "assay:1"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["midified incubator at 37 °C with 5% CO2. All cell lines were maintained in a mycoplasma-free state, and mycoplasma d", "Table 3 of the Supplementary materials. All cell lines were maintained in a mycoplasma-free state. At the end of ea", "ing. 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