HDAC9 promotes atherosclerosis by suppressing CYP7A1 and impairing hepatic cholesterol excretion

Histone deacetylase 9 (HDAC9) exacerbates atherosclerosis through inflammatory pathways, yet its specific role in cholesterol metabolism remains to be fully elucidated. Here, we investigated whether HDAC9 promotes atherosclerosis by impairing hepatic cholesterol excretion via bile acid synthesis. Using ApoE-/-and ApoE-/-PSRC1-/- mice fed a high-fat diet (HFD), we observed that PSRC1 deficiency or HFD feeding upregulated hepatic HDAC9 expression, concomitant with suppression of the rate-limiting bile acid enzyme CYP7A1. Pharmacological inhibition of HDAC9 (TMP195) or liver-targeted AAV8-shHdac9 knockdown restored CYP7A1 expression, reduced plasma LDL-C, and attenuated aortic plaque burden in HFD-fed ApoE-/- mice. In vitro assays in Hep1-6 and HepG2 hepatocytes confirmed that Hdac9 knockdown attenuated free fatty acid-induced cholesterol accumulation, while overexpression exacerbated it. Mechanistically, HDAC9 transcriptionally represses Cyp7a1, as the cholesterol-lowering effect of Hdac9 knockdown was abolished by concomitant Cyp7a1 silencing. Collectively, our findings indicate that HDAC9 promotes atherosclerosis by transcriptionally repressing Cyp7a1 and impairing bile acid synthesis, independent of its inflammatory roles. These results highlight hepatic HDAC9 as a promising therapeutic target for hypercholesterolemia and advocate for the development of liver-directed HDAC9 inhibitors.