ECM1 protects against liver steatosis through PCBP1-mediated iron homeostasis

Background and Aims: Extracellular matrix protein 1 (ECM1) is known to inhibit transforming growth factor β (TGF-β) signalling and hepatic stellate cells (HSCs) activation, thereby attenuating liver fibrosis. RNA-seq profiling of livers from wild-type (WT) and Ecm1-deficient mice revealed different enrichments in metabolic changes in fatty acid synthesis and inflammatory pathways, suggesting a regulatory role for ECM1 in liver steatosis. Here, we studied the role of ECM1 in metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis and underlying mechanisms. Approach and Results: Hepatic ECM1 expression was evaluated and found to be significantly reduced in liver samples from patients with metabolic dysfunction-associated steatohepatitis (MASH), and in four established MASH mouse models (HFD, MCD, HFHC, and ob/ob -/- ). Although overexpression of ECM1 effectively blocked hepatic insulin resistance, steatosis, and inflammation, ECM1 ablation exacerbated diet-induced MASH progression. Mechanistically, ECM1 interacted with the K-Homology 3 (KH3) domain of poly rC binding protein 1 (PCBP1) to suppress iron overload, mitigating lipid peroxidation and consequently impeding metabolic dysfunction-associated steatohepatitis (MASH) advancement under metabolic stress. Re-expression of ECM1 and PCBP1 ameliorated liver disease progression. Conclusion: Our study reveals that ECM1 is a critical regulator in MASH, modulating lipid peroxidation by maintaining PCBP1-mediated intracellular iron homeostasis. Targeting ECM1 to restore PCBP1-dependent iron homeostasis may offer a novel therapeutic avenue for MASH.