Elevated malonic acid and 15d-PGJ2 in MASLD rats with diabetes triggered pathological cardiac remodeling through impairment of mitochondrial health and cellular metabolism

Metabolic dysfunction-associated steatotic liver disease (MASLD) significantly raises the risk of cardiovascular disease (CVD) and makes it the leading cause of death in affected individuals. Despite growing evidence, the liver-heart connection remains poorly understood. MASLD was induced in male SD rats using an 8-week high-fat diet along with a single streptozotocin dose at week 6. Cardiac changes were assessed by echocardiography, electrocardiography, and histopathology. Two altered metabolites identified by LC-MS/MS were evaluated in cardiomyoblasts (MTT, JC-1, MitoSOX, & Seahorse) and in rats to assess cardiac structure and function. MASLD rats with diabetes exhibited increased LV mass, wall thickness, diastolic diameter, and volume, with reduced ejection fraction, fractional shortening, cardiac output, and stroke volume. Histology confirmed cardiomyocyte hypertrophy, fibrosis, and hepatic lipid accumulation. LC-MS/MS identified elevated malonic acid and 15-deoxy-12,14-prostaglandin J2 (15d-PGJ2) in serum. In cardiomyoblasts, these metabolites increased mitochondrial ROS, reduced membrane potential, and decreased metabolites such as taurine, arginine, succinate, and l-glutamine. Eight weeks of in vivo treatment with malonic acid and 15d-PGJ2 induced pathological cardiac remodeling, fibrosis, and subendocardial ischemia. Metabolite-treated hearts also showed an increase in inosine and 12R-HETE, with reduced isovaleric acid, creatine, proline, and N-acetyl-L-histidine. Altered cardiac structure and function in MASLD rats were associated with elevated serum malonic acid and 15d-PGJ2, which impair mitochondrial homeostasis and cellular metabolism. These findings support a liver-heart axis and highlight potential therapeutic targets for MASLD-related CVD.