m1A-mediated regulation of BIRC2 mRNA stability drives apoptosis evasion and tumor progression in liver cancer

Abstract Liver cancer remains one of the leading causes of cancer-related mortality worldwide, with its progression driven by uncontrolled cell proliferation and evasion of apoptosis. N1-methyladenosine (m 1 A) is a prevalent RNA modification implicated in cancer progression, yet its role in liver cancer remains unclear. Here, we report a significant reduction in m 1 A levels in liver cancer tissues, which contributes to apoptosis evasion in liver cancer cells. We demonstrate that ALKBH3, an m 1 A demethylase, regulates apoptosis by modulating BIRC2 expression. Specifically, ALKBH3 depletion destabilizes BIRC2 mRNA by promoting its degradation, facilitated by m 1 A modifications at positions A98/99/100 in the 5'-UTR of BIRC2. These modifications enhance the interaction between BIRC2 mRNA and the YTHDF3/CNOT1–XRN2 complex, thereby driving mRNA degradation. In vitro, in vivo, and clinical analyses validate the critical role of the m 1 A/BIRC2 axis in regulating apoptosis and tumor progression in liver cancer. Our findings underscore the therapeutic potential of targeting the m 1 A/BIRC2 axis to overcome apoptosis resistance in liver cancer, offering new avenues for intervention in this malignancy.