Bariatric surgery resolves MASH by enhancing MAT1A-dependent one-carbon metabolism

Bariatric surgery shows variable efficacy in resolving metabolic dysfunction-associated steatohepatitis (MASH), with mechanisms underlying therapeutic heterogeneity remaining unclear. Using multiple male murine MASH models, we demonstrate that vertical sleeve gastrectomy (VSG) ameliorates hepatic steatosis and fibrosis through mechanisms that extend beyond weight loss. Multi-omic profiling reveals VSG enhances hepatic one-carbon metabolism (1CM) via upregulation of methionine adenosyltransferase 1 A (MAT1A), increasing S-adenosylmethionine (SAM) availability and the SAM/SAH ratio. This metabolic reprogramming restores hepatic phosphatidylcholine (PC) /phosphatidylethanolamine (PE) homeostasis, alleviating endoplasmic reticulum stress and mitochondrial dysfunction. Critically, dietary depletion of one-carbon substrates or genetic ablation of MAT1A abolishes VSG's therapeutic effects, while betaine supplementation rescues surgical efficacy. In humans, paired liver biopsies from patients with MASH (n = 4) show MAT1A upregulation correlating with histological improvement, while plasma metabolomics from a separate cohort (n = 42) reveals that patients with poor hepatic response to VSG display compromised one-carbon metabolism signatures, with SAM levels correlating with therapeutic response. These findings establish MAT1A-mediated methylation as an essential mechanism for optimal VSG efficacy in preclinical models and identify one-carbon metabolites as candidate biomarkers for predicting surgical response, suggesting that preoperative metabolic profiling could guide methyl donor supplementation to optimize VSG outcomes in MASH.