Neonatal liver-derived FTH1-enriched extracellular vesicles attenuate ferroptosis and ameliorate MASLD pathogenesis

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), a leading cause of chronic liver pathology, lacks effective therapies. This study identifies ferroptosis—a lipid peroxidation-driven, iron-dependent form of cell death—as a central pathogenic mechanism in MASLD. Integrative proteomic and histopathological analyses of human and murine MASLD livers revealed marked ferroptosis activation, characterized by dysregulated iron metabolism (reduced FTH1 and GPX4; elevated ACSL4) and oxidative stress. To address this, neonatal liver-derived extracellular vesicles (EVnew) enriched with FTH1, were evaluated as a therapeutic strategy. EVnew exhibited superior biodistribution to adult-derived EVs (EVadult), with liver-specific tropism and proteomic enrichment of FTH1, mitochondrial proteins, and glutathione regulators. In MASLD models, EVnew administration attenuated hepatic injury, steatosis, and fibrosis, outperforming EVadult by restoring iron homeostasis via FTH1-mediated suppression of lipid peroxidation. Specifically, EVnew upregulated NRF2 and GPX4 while downregulating ACSL4 and HSP60. Neutralizing FTH1 abolished the protective effects of EVnew in vitro, confirming that FTH1 is the key mediator. These findings establish ferroptosis as a therapeutic target in MASLD and highlight the dual capacity of EVnew to inhibit ferroptosis. This work pioneers xenogeneic EVs-based therapy for metabolic liver diseases, offering a novel multifaceted intervention with translational potential.