ECM1 protects against liver steatosis through PCBP1-mediated iron homeostasis
Danyan Zhang, Ayiguzhali Abulitipu, Pengcheng Pang, Lei Bai, Rui Li, Shaliyan Tuerxunmaimaiti, Wen Chen, Shuangfeng Chen, Houkun Lv, Yadong Fu, Qizhen Du, Fuquan Jin, Chunyan Yi, Yangmin Hao, Liyan Ma, Jingsong Li, Zhiyang Ling, Yaguang Zhang, Liang Zhao, Weiguo Fan, Guoli Du, Bing Sun
Abstract
BACKGROUND AND AIMS: Extracellular matrix protein 1 (ECM1) is known to inhibit transforming growth factor β signalling and HSC activation, thereby attenuating liver fibrosis. RNA-seq profiling of livers from wild-type 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 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 4 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 r(C) binding protein 1 (PCBP1) to suppress iron overload, mitigating lipid peroxidation and consequently impeding MASH advancement under metabolic stress. Re-expression of ECM1 and PCBP1 ameliorated liver disease progression. CONCLUSIONS: 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.