Integrin beta-like 1 protects against liver injury by inhibiting ferroptosis in metabolic dysfunction-associated steatohepatitis.

Background

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Aims

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by hepatic lipid accumulation, inflammation, and oxidative injury. However, the regulatory role of integrin beta-like 1 (ITGBL1) in MASH remains unknown.

Methods

ITGBL1 knockout (KO) and liver-specific overexpressing mice were fed an MCD diet for 4 weeks. In vitro, AML‑12 hepatocytes were treated with palmitic acid (PA), with ITGBL1 overexpression (OE) or knockdown (sgITGBL1). Liver injury, steatosis, inflammation, and ferroptosis markers were assessed by biochemical assays, histology, RNA‑seq, western blotting, and transmission electron microscopy.

Results

ITGBL1‑KO mice exhibited exacerbated liver injury, steatosis, inflammation, and fibrosis, whereas ITGBL1 overexpression ameliorated these pathological changes. Mechanistically, ITGBL1 deficiency disrupted hepatic iron homeostasis, leading to iron overload, lipid peroxidation, and oxidative stress, with concomitant downregulation of the ferroptosis defense proteins GPX4 and SLC7A11 and upregulation of the pro‑ferroptotic enzyme ACSL4. ITGBL1 ablation also elevated Lipocalin-2 (LCN2) expression, which inversely correlated with ITGBL1 levels. In PA‑treated hepatocytes, ITGBL1 overexpression reversed ferroptotic protein alterations, while ITGBL1 knockdown exacerbated them. Ferrostatin-1 (Fer-1) alleviated the exacerbated ferroptotic damage in ITGBL1‑deficient cells, with reduced lipid peroxidation and preserved mitochondrial morphology.

Conclusion

In conclusion, this study establishes ITGBL1 as an endogenous suppressor of hepatocyte ferroptosis in MASH, acting through regulation of iron homeostasis and lipid peroxidation. These findings suggest that targeting ITGBL1 may offer a valuable therapeutic strategy for MASH and potentially other ferroptosis-related liver diseases.