ECM1 protects against liver steatosis through PCBP1-mediated iron homeostasis.

Abstract

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.