HMGCS2-mediated ketogenesis maintains intestinal barrier in inflammatory bowel disease by inhibiting ferroptosis

Abstract Complete mucosal healing is a key therapeutic goal in inflammatory bowel disease (IBD). While ferroptosis-mediated epithelial cell death is known to compromise the mucosal barrier as the cornerstone of mucosal healing, the precise mechanisms driving this process during IBD pathogenesis remain to be fully elucidated. In this study, we discover that the mitochondrial metabolic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase-2 (HMGCS2) expression is downregulated in the inflamed intestinal tissues of patients with IBD and in colitis mice. Intestinal epithelial-specific Hmgcs2 knockout ( Hmgcs2 INT-KO ) accelerates colitis progression and disrupts the mucosal barrier. Hmgcs2 INT-KO mice exhibit characteristic ferroptotic mitochondrial changes and elevated lipid reactive oxygen species and iron. Ketone ester (KE), the extra supplement of HMGCS2 product β-hydroxybutyrate (BHB), reverses the effects of Hmgcs2 deficiency on epithelial ferroptosis and the mucosal barrier in colitis. Mechanistically, HMGCS2 functions as a metabolic regulator that upregulates protein kinase C epsilon (PKC-ε) expression via histone H3 lysine 9 β-hydroxybutyrylation (H3K9bhb). This epigenetic event triggers the PKC-ε/YAP/TFRC axis to inhibit ferroptosis and safeguard the mucosal barrier. Thus, HMGCS2-mediated ketogenesis protects the intestinal mucosal barrier by epigenetically inhibiting epithelial ferroptosis, highlighting HMGCS2 as a promising therapeutic target in IBD.