Sex-based multiomics analysis uncovers metabolic and molecular mediators linking MASH and atherosclerosis

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in patients with metabolic dysfunction-associated steatohepatitis (MASH). No therapy currently targets both diseases simultaneously, and a major hurdle for discovering new treatments is the lack of animal models that recapitulate both diseases, especially in females.  Male and female Ldlr-/- mice were fed a Western diet (WD), modified choline-deficient high-fat diet (mCDHFD), or modified MASH-inducing diet (mMASHD) containing equivalent physiological levels of cholesterol. Comprehensive multiomics including metabolomics, lipidomics, and transcriptomics alongside histopathological and biochemical analyses were integrated to characterize concurrent MASH and atherosclerosis. Liver transcriptomes of mice were integrated with those of patients with MASH. Our sex-based multiomics analysis established a translational murine model of concurrent MASH and atherosclerosis, revealing sex-specific dietary responses, and metabolic and transcriptional pathways as potential biomarkers and therapeutic targets.