FTO-mediated m6A regulation modulates hepatic stellate cell activation through the IGF2BP1–TRIB3 axis and mitochondrial homeostasis
Year: 2026
Type: article
Abstract: Liver fibrosis represents a critical pathological stage in chronic liver diseases, though its pathogenesis remains incompletely understood—particularly the role of N 6-methyladenosine (m6A) methylation. This study investigates the mechanism by which the m6A demethylase fat mass and obesity-associated protein (FTO) regulates hepatic stellate cell (HSC) activation and liver fibrosis. A murine liver fibrosis model was established using bile duct ligation (BDL), and human hepatic stellate LX-2 cells were transfected with specific shRNAs or overexpression plasmids to modulate FTO and IGF2BP1 expression. Techniques included histology (H&E, Sirius Red, Masson’s trichrome), immunohistochemistry (IHC), immunofluorescence, Western blotting, qRT-PCR, RNA dot blot, MeRIP-qPCR, and mitochondrial functional assays to assess collagen deposition, HSC activation, m6A methylation levels, and mitophagy. BDL mice exhibited significant inflammatory infiltration and collagen deposition, indicating HSC activation. Western blot and qPCR revealed downregulated FTO expression in HSCs. FTO deficiency promoted HSC activation by elevating m6A levels, increasing expression of α-smooth muscle actin (α-SMA), collagen type I (Collagen I), and transforming growth factor-β (TGF-β). Mechanistically, FTO depletion was associated with increased TRIB3 expression through an m6A–insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)-dependent regulatory mechanism, accompanied by mitochondrial dysfunction, mitophagy-related alterations, and HSC activation. These findings suggest that dysregulation of the FTO–m6A–IGF2BP1–TRIB3 axis contributes to hepatic stellate cell activation and liver fibrosis, highlighting this pathway as a potential target for epigenetic intervention and the development of mechanism-based therapeutic strategies for liver fibrosis.
Source: Scientific Reports
Institutions: Xinxiang Central Hospital, Henan Medical University
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,690
OpenAlex ID: W7223573242