Abstract / Summary
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly recognized as systemic cardiometabolic disorders rather than isolated liver diseases. Cardiovascular disease (CVD) represents the leading cause of mortality in patients with MASLD/MASH, highlighting the need for therapeutic strategies that address both hepatic and cardiovascular risk. MASLD/MASH and CVD are connected through a network of interdependent mechanisms, including adipose tissue dysfunction, insulin resistance, altered insulin–glucagon signaling, atherogenic dyslipidemia, lipotoxicity, mitochondrial and endoplasmic reticulum stress, innate immune activation, chronic inflammation, endothelial dysfunction, thrombogenic signaling, and dysregulated hepatokine and adipokine pathways. These mechanisms provide potential therapeutic entry points across the liver–adipose tissue–vascular axis. Lifestyle modification and conventional cardiometabolic therapies remain foundational, while several pharmacological agents increasingly target specific components of this network. We summarize the mechanistic rationale and clinical evidence for emerging therapies, including glucagon-like peptide-1 receptor agonists, dual incretin agonists, fibroblast growth factor 21 analogs, thyroid hormone receptor-β agonists, peroxisome proliferator-activated receptor agonists, and agents targeting de novo lipogenesis. We further discuss why residual metabolic, inflammatory, and fibrogenic activity may limit monotherapy and how mechanism-based combination therapy could improve efficacy while mitigating treatment-related metabolic liabilities. Finally, we outline future priorities, including biomarker-guided patient selection, longitudinal noninvasive monitoring, integrated hepatic–cardiovascular trial endpoints, adaptive combination strategies, and development of therapies targeting immune, fibrogenic, and inter-organ signaling pathways.