Iron overload in steatotic hepatocytes drives systemic metabolic dysfunction via alterations in hepatokine production.

Iron overload has emerged as a significant risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), a growing global health concern. Despite this association, the precise mechanisms by which hepatic iron and its regulatory genes connect liver pathology to systemic metabolic dysfunction remain elusive. Here, we demonstrate that humoral signals originating from iron-overloaded hepatocytes acted as critical mediators driving systemic metabolic dysfunction in MASLD. Ferroportin (FPN, SLC40A1), the sole cellular iron exporter, exhibited markedly reduced expression in hepatocytes of both patients with MASLD and mouse models of the disease, concomitant with hepatic iron accumulation. Functionally, hepatocyte-specific FPN deletion significantly exacerbated diet-induced obesity and insulin resistance, with these metabolic perturbations accompanied by decreased energy expenditure and impaired thermogenic capacity. Mechanistically, we establish that hepatic iron accumulation resulting from FPN deficiency enhanced the production of 2 specific hepatokines, fetuin-A and LECT2, through activation of the transcription factor FoxO1. Notably, therapeutic interventions - including genetic silencing of these hepatokines, hepatocyte-specific FPN overexpression, or oral iron chelation - effectively reversed the metabolic dysfunction phenotypes. These findings provide critical insights into the pathophysiological mechanisms linking MASLD to systemic metabolic disorders and highlight promising therapeutic strategies to combat these diseases.