Convergent ferroptosis and pyroptosis in MASLD-associated cardiac remodeling

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects ∼30% of the global population and is associated with increased risks of heart failure (particularly heart failure with preserved ejection fraction), atrial fibrillation, and cardiovascular mortality. Despite well-established epidemiological links between MASLD and cardiovascular disease, the molecular pathways driving MASLD-related cardiac remodeling remain incompletely understood. This state-of-the-art mini review examines ferroptosis and pyroptosis as potentially convergent regulated cell-death pathways relevant to both the steatotic liver and the remodeling heart. Ferroptosis is an iron-dependent, lipid peroxidation-driven cell death that mediates hepatocyte injury in experimental MASLD and contributes to cardiomyocyte injury under cardiac stress. Pyroptosis is an inflammasome-mediated pro-inflammatory cell death executed by gasdermin D, which amplifies tissue inflammation in hepatic and cardiac disease. Direct preclinical evidence from a pressure-overload heart-failure model demonstrates ferroptosis-to-pyroptosis signaling through the ACSL4/ALOX12/12-HETE/NLRP3 axis; however, this cascade has not yet been directly validated in MASLD models or in patients with MASLD-associated cardiac remodeling. We therefore distinguish experimentally established within-organ mechanisms from hypothesized interorgan liver-heart links, highlight shared regulators including reactive oxygen species, the cGAS/STING pathway, and the NRF2 hub, and discuss translational strategies and evidence gaps that should guide future validation.