Cardio-hepatic axis in metabolic dysfunction-associated steatotic liver disease: Mechanisms, clinical implications and therapeutic opportunities

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the predominant hepatic manifestation of systemic metabolic dysfunction and an independent risk factor for cardiovascular disease. Recent evidence supports the cardio-hepatic axis as a bidirectional communication network between the liver and the cardiovascular system. In MASLD, the liver releases lipotoxic metabolites, hepatokines, and extracellular vesicles that contribute to endothelial dysfunction, vascular inflammation, atherosclerotic plaque progression, and adverse myocardial remodeling; conversely, cardiac dysfunction promotes liver injury and fibrosis via venous congestion and neurohumoral activation. Systemic inflammation, gut dysbiosis, and genetic susceptibility collectively constitute amplification networks of the cardio-hepatic axis, establishing MASLD as a cardiometabolic disorder. Liver fibrosis severity and cardiovascular risk demonstrate a parallel relationship in MASLD patients. We propose a risk stratification framework integrating liver fibrosis screening into cardiovascular risk assessment. Therapeutically, the approach shifts from single-organ targeting to systemic cardio-hepatic axis modulation, with multiple regimens exerting dual effects on both organs. This review synthesizes current evidence on the mechanisms, risk stratification, and therapeutic approaches of the cardio-hepatic axis in MASLD, providing a conceptual roadmap for cardio-hepatic comorbidity.

Keywords: Metabolic dysfunction-associated steatotic liver disease; Cardio-hepatic axis; Cardiovascular disease; Risk stratification; Therapeutic strategies

Core Tip: Metabolic dysfunction-associated steatotic liver disease is a systemic cardiometabolic disorder driven by the cardio-hepatic axis. This review examines bidirectional signaling and systemic amplification networks within this axis and explores its intrinsic mechanisms. Based on population evidence, we propose a risk stratification framework that integrates metabolic dysfunction-associated steatotic liver disease evaluation into cardiovascular risk assessment, shifting management from a liver-centric to a systemic cardio-hepatic co-management model. We also critically appraise therapeutic strategies targeting these mechanisms according to clinical evidence strength. However, key challenges remain, including the liver-heart causal relationship, the lack of a risk assessment system capturing cardio-hepatic crosstalk, and the limited availability of axis-specific randomized controlled trials.