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. 2025 May 15.
doi: 10.1097/HEP.0000000000001402. Online ahead of print.

ECM1 protects against liver steatosis through PCBP1-mediated iron homeostasis

Danyan Zhang  1   2 , Ayiguzhali Abulitipu  3 , Pengcheng Pang  1   2 , Lei Bai  4 , Lian Liu  2 , Shaliyan Tuerxunmaimaiti  3 , Wen Chen  2 , Shuangfeng Chen  1   2 , Houkun Lv  1 , Yadong Fu  2 , Qizhen Du  2 , Fuquan Jin  2 , Chunyan Yi  2 , Yangmin Hao  3 , Liyan Ma  2 , Jinsong Li  1   2 , Zhiyang Ling  2 , Yaguang Zhang  5 , Liang Zhao  3   6 , Weiguo Fan  2 , Guoli Du  3   7 , Bing Sun  1   2   3
Affiliations

ECM1 protects against liver steatosis through PCBP1-mediated iron homeostasis

Danyan Zhang et al. Hepatology. .

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.

Keywords: extracellular matrix protein 1; iron overload; metabolic dysfunction–associated steatohepatitis; poly rC binding protein 1.

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