Time-restricted feeding exacerbates liver fibrosis by promoting BDH1-mediated ketolysis in hepatic stellate cells.
Time-restricted feeding (TRF) is widely considered metabolically beneficial, yet its impact on chronic liver disease progression remains poorly defined. This study investigates the effects of TRF on liver fibrogenesis. Using carbon tetrachloride (CCl4)-induced, bile duct ligation (BDL)-induced, and choline-deficient, L-amino acid-defined high-fat diet (CDAHFD)-induced murine models of liver fibrosis, we demonstrate that TRF consistently exacerbates fibrotic injury. Mechanistically, TRF induces the systemic elevation of the ketone body {beta}-hydroxybutyrate (BHB). We identify the ketolytic enzyme 3-hydroxybutyrate dehydrogenase 1 (BDH1) as a critical mediator of this process within hepatic stellate cells (HSCs). BDH1 expression is markedly upregulated in activated HSCs, enabling these cells to metabolize BHB. This BDH1-dependent ketolysis redirects BHB-derived carbons into the tricarboxylic acid cycle, supplying acetyl-CoA and citrate to drive de novo lipogenesis and support a profibrogenic metabolic state. Both the genetic ablation of Bdh1 specifically in HSCs and the inhibition of hepatic ketogenesis successfully abolished the pro-fibrotic effects of TRF and exogenous BHB administration. Conversely, exogenous BHB alone was sufficient to recapitulate the exacerbated fibrotic phenotype observed with TRF. These findings reveal a context-dependent, detrimental role for TRF during chronic liver injury, driven by BDH1-mediated metabolic reprogramming in HSCs. Consequently, dietary interventions that elevate systemic ketone bodies should be approached with caution in the setting of active liver fibrosis.