Oxidative stress-driven m5C methylation by NSUN5 confers cisplatin resistance in lung adenocarcinoma through promoting glycolysis

C-modified transcript. Ultimately, NSUN5 enhances glucose uptake in a GLUT1-dependent manner, leading to increased glycolysis and thereby promoting homologous recombination (HR) repair. Functional studies confirmed that NSUN5 knockdown sensitized LUAD cells to cisplatin through increasing DNA damage, whereas its exogenous expression produced opposite effects. Crucially, silencing GLUT1 partially reversed NSUN5-mediated cisplatin resistance in vitro and in vivo. In summary, NSUN5 acts as a key translator that converts oxidative stress signals into enhanced HR repair by modulating the Warburg effect, thus highlighting its therapeutic potential for overcoming acquired chemoresistance in LUAD.