Work

MFAP4 Deficiency Attenuates Liver Fibrosis by Regulating Hepatic Stellate Cell Fate Through Inhibition of the FAK/PI3K/NFκB Signaling Pathway

Year: 2025

Type: article

Abstract: BACKGROUND & AIMS: Liver fibrosis, driven by chronic injury, hinges on hepatic stellate cells (HSCs) activation. Microfibrillar-associated protein 4 (MFAP4), an extracellular matrix protein critical for elastic fiber assembly, is up-regulated in hepatic fibrosis, yet its mechanistic role remains unclear. METHODS: and TAA, whereas LX-2 cells were activated with transforming growth factor-β1. Bioinformatics analysis, histopathology, double immunofluorescence, flow cytometry, Transwell coculture systems, Western blot, and quantitative polymerase chain reaction were used to identify the primary intrahepatic cell types expressing MFAP4 and assess its effects on HSCs activation and apoptosis. RESULTS: - and TAA-induced liver fibrosis. Mechanistic analysis reveals that MFAP4 binds to integrin αvβ3 on the HSCs membrane, activating the FAK/PI3K/NFκB signaling pathway, which promotes HSC activation and survival, ultimately exacerbating liver fibrosis. Moreover, MFAP4 mediates a self-sustaining feedback loop via integrin αvβ3, maintaining HSCs activation and further promoting fibrosis progression. CONCLUSIONS: MFAP4 governs HSCs activation and apoptosis resistance via integrin αvβ3-dependent FAK/PI3K/NFκB signaling. Targeting MFAP4 mitigates fibrosis by altering HSCs fate.

Source: Cellular and Molecular Gastroenterology and Hepatology

DOI: 10.1016/j.jcmgh.2025.101548