N⁶-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells

Area of Science:

• Cell Death Mechanisms
• Epigenetics and RNA Biology
• Hepatology and Liver Disease

Background:

• Ferroptosis, a distinct cell death pathway driven by iron-dependent lipid peroxidation, has poorly understood mechanisms.
• Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis, and targeting their death pathways is a therapeutic strategy.

Purpose of the Study:

• To elucidate the role of N⁶-methyladenosine (m⁶A) modification in ferroptosis of HSCs.
• To identify molecular players involved in m⁶A-mediated ferroptosis and its therapeutic potential in liver fibrosis.

Main Methods:

• RNA sequencing (RNA-seq) to analyze m⁶A modification patterns.
• Investigated the role of METTL4, FTO, and YTHDF1 in m⁶A regulation and ferroptosis.
• Utilized cell culture models and in vivo mouse models of liver fibrosis.
• Retrospective analysis of patient data from HCC patients treated with sorafenib.

Main Results:

• m⁶A levels increased upon ferroptosis induction due to METTL4 upregulation and FTO downregulation.
• m⁶A modification stabilized BECN1 mRNA, promoting autophagy and HSC ferroptosis, with YTHDF1 identified as the key reader protein.
• Erastin treatment induced HSC ferroptosis and alleviated liver fibrosis in mice, an effect impaired by inhibiting m⁶A modification.
• Upregulation of m⁶A, autophagy, and ferroptosis was observed in human HSCs from HCC patients.

Conclusions:

• m⁶A modification is a critical regulator of ferroptosis in HSCs, primarily through stabilizing BECN1 mRNA via YTHDF1.
• Targeting m⁶A-dependent ferroptosis presents a promising therapeutic strategy for liver fibrosis.
• The findings reveal novel molecular mechanisms underlying ferroptosis and its connection to epigenetic modifications.