Abstract Body: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most prevalent form of liver disease, affecting one-third of the global population with limited treatment available. MASLD is a spectrum of liver diseases that initiates from simple hepatic steatosis and progresses towards metabolic dysfunction-associated steatohepatitis (MASH). MASH is characterized by lobular inflammation and hepatic fibrosis, and if left untreated progresses to cirrhosis. While MASH is associated with an elevated risk of liver-related mortality, the leading cause of death in patients with MASH is atherosclerotic cardiovascular disease. Importantly, no current therapy targets both MASH and atherosclerosis simultaneously. A key challenge in developing new treatments is the lack of animal models that mimic both diseases simultaneously, especially in females. To address this challenge and to establish a useful model of concurrent MASH and atherosclerosis, we utilized both male and female Ldlr-/- mice, combined with different dietary regimens containing equal and physiologically relevant cholesterol levels. These included a Western Diet (WD), modified choline-deficient high-fat diet (mCDHFD), and modified MASH diet (mMASHD), all which were compared with a standard low-fat diet. Using a multiomics approach that integrates metabolomics, lipidomics, and transcriptomics with histopathological and biochemical analyses, we report the development of a murine model that concurrently features MASH and atherosclerosis. This model displays transcriptomic signatures comparable to those of human disease and reveals sexual dimorphism in response to different dietary regimens. Notably, we identified novel metabolites (arginine, glycine, itaconate, and sphinganine), and key genes (Trem2, Ccl2, and Cd52) implicated in both diseases. The use of this model will be instrumental in advancing our understanding of the shared pathophysiology of MASH and atherosclerosis and in facilitating the development of dual therapeutic approaches.