| First Author | Liao X | Year | 2025 |
| Journal | Hepatol Commun | Volume | 9 |
| Issue | 8 | PubMed ID | 40658786 |
| Mgi Jnum | J:389938 | Mgi Id | MGI:8369472 |
| Doi | 10.1097/HC9.0000000000000752 | Citation | Liao X, et al. (2025) METTL3 inhibits liver fibrosis via RBX1 stability and TXNIP-mediated ferroptosis. Hepatol Commun 9(8) |
| abstractText | BACKGROUND: Clinical treatment of liver fibrosis remains a significant challenge, necessitating the identification of molecules and factors capable of preventing or slowing its progression to develop more effective therapeutic targets. This study focuses on the pivotal role of the thioredoxin-interacting protein (TXNIP) in the onset of liver fibrosis and the significant contribution of ferroptosis, initiated by autophagy processes, in mitigating liver fibrosis. Despite this, the precise biological functions and mechanisms of TXNIP-mediated autophagy-dependent ferroptosis in the context of liver fibrosis are not fully understood. METHODS: To address these gaps, we utilized a combination of bioinformatics analysis, real-time PCR, western blot, and immunohistochemistry to identify markers associated with liver fibrosis and to assess the roles of TXNIP-mediated autophagy-dependent ferroptosis and RNA methylation in the disease's progression. Two models of liver fibrosis, induced by CCl4 and bile duct ligation, were employed to investigate the regulatory effect of METTL3 on RBX1 mRNA stability and the consequent impact on liver fibrosis. RESULTS: Our findings demonstrate that METTL3 upregulates RBX1 expression by enhancing the stability of RBX1 mRNA. The increased RBX1 functions as an E3 ligase for TXNIP, facilitating TXNIP ubiquitination and reducing its expression, which subsequently initiates cell ferroptosis and aids in the improvement of liver fibrosis. CONCLUSIONS: This study underscores the essential role of TXNIP in the progression of liver fibrosis and suggests that a therapeutic strategy targeting TXNIP ubiquitination-mediated autophagy-dependent ferroptosis could offer a novel approach to treating liver fibrosis. The insights gained from this research provide a solid foundation for the development of innovative therapeutic interventions. |
