FOXS1 Promotes Liver Fibrosis Through TGF-β1/Smad Signaling: Targeting a Novel miR-212-5p/FTO Axis

Area of Science:

• Hepatology
• Molecular Biology
• Biochemistry

Background:

• Liver fibrosis is characterized by excessive extracellular matrix deposition, driven by hepatic stellate cell (HSC) activation.
• The role of Forkhead box S1 (FOXS1) in hepatic fibrosis and its regulatory mechanisms are not well understood.

Purpose of the Study:

• To investigate the functional role of FOXS1 in hepatic fibrosis.
• To elucidate the regulatory mechanisms underlying FOXS1's function in HSC activation and liver fibrosis.

Main Methods:

• Analysis of FOXS1 expression in human fibrotic liver tissues and mouse models (CCl4-induced and MCD diet-induced NASH).
• In vivo and in vitro studies using CCl4-induced and MCD mouse models, TGF-β1-stimulated cells (LX-2, HSC-T6), and primary HSCs to assess FOXS1 function.
• Molecular assays including luciferase reporter, RNA pulldown, MeRIP, and RIP to explore regulatory relationships between FOXS1, miR-212-5p, and FTO.

Main Results:

• FOXS1 expression is elevated in fibrotic livers and correlates with fibrosis severity.
• FOXS1 knockdown ameliorates liver fibrosis, reduces ECM deposition, and improves liver function in mice.
• FOXS1 promotes HSC activation, migration, and apoptosis resistance via a positive feedback loop with TGF-β1/Smad signaling.
• FTO-mediated m6A demethylation inhibits miR-212-5p maturation, while FTO knockdown suppresses FOXS1 and exerts antifibrotic effects.

Conclusions:

• FOXS1 is a novel driver of hepatic fibrosis, promoting HSC activation through a TGF-β1/Smad-dependent feedback loop.
• The FTO/miR-212-5p/FOXS1 axis represents a promising therapeutic target for liver fibrosis treatment.