METTL3 confers oxaliplatin resistance through the activation of G6PD-enhanced pentose phosphate pathway in hepatocellular carcinoma.

ABSTRACT: Oxaliplatin-based therapeutics is a widely used treatment approach for hepatocellular carcinoma (HCC) patients; however, drug resistance poses a significant clinical challenge. Epigenetic modifications have been implicated in the development of drug resistance. In our study, employing siRNA library screening, we identified that silencing the m⁶A writer METTL3 significantly enhanced the sensitivity to oxaliplatin in both in vivo and in vitro HCC models. Further investigations through combined RNA-seq and non-targeted metabolomics analysis revealed that silencing METTL3 impeded the pentose phosphate pathway (PPP), leading to a reduction in NADPH and nucleotide precursors. This disruption induced DNA damage, decreased DNA synthesis, and ultimately resulted in cell cycle arrest. Mec

SUBMITTER: Jin X 

PROVIDER: S-EPMC11894169 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature