Metabolic Dysfunction-Associated Steatotic Liver Disease as a Systemic Driver of Heart Failure With Preserved Ejection Fraction: Mechanistic Insights and Emerging Therapeutic Perspectives.

Heart failure with preserved ejection fraction (HFpEF) has emerged as the predominantform of heart failure (HF) worldwide and is increasingly recognized as a systemic syndrome closely linked to metabolic dysfunction. Furthermore, metabolic dysfunction-associated steatotic liver disease (MASLD), a highly prevalent yet often underrecognized comorbidity in patients with HFpEF, has attracted increasing attention. Accumulating epidemiological evidence demonstrates a significant association between MASLD and HFpEF, suggesting shared pathophysiological foundations that extend beyond coincidental coexistence. Mechanistically, MASLD contributes to the development and progression of HFpEF through a network of interconnected pathways, including chronic low-grade inflammation, insulin resistance (IR), dysregulated lipid metabolism, endothelial dysfunction, the gut-liver-heart axis, and as liver-derived mediators that influence cardiac structure and function. These overlapping mechanisms underlie the pronounced clinical and phenotypic heterogeneity of HFpEF and may help explain the limited efficacy of conventional heart failure therapies. This review summarizes current diagnostic and therapeutic strategies for HFpEF and MASLD and proposes an integrated, multiorgan framework to improve clinical recognition and management. A deeper understanding of liver-heart interactions is essential to redefining cardiometabolic disease, shifting from an organ-centric perspective toward a more integrated, mechanism-based approach.