NCAPG confers ferroptosis resistance of hepatocellular carcinoma through NSUN2-mediated m5C modification

Ferroptosis is considered as a promising strategy for treatment of hepatocellular carcinoma (HCC) due to its susceptibility. However, ferroptosis-based treatment is rarely discussed in clinical application, which is closely correlated with insufficient exploration toward the upstream mechanisms of ferroptosis and corresponding biomarkers. Non-SMC condensin I complex subunit G (NCAPG) is an oncogene in many human cancer types, including HCC, while its effect on HCC ferroptosis is still unknown. In the present study, we reported NCAPG promoted ferroptosis resistance of HCC in vivo and in vitro. Further, NCAPG conferred ferroptosis resistance by regulating GPX4 expression both in mRNA and protein level. Mechanistically, NCAPG protein interacted with NSUN2 protein at its 446aa-460aa and inhibited its protein degradation. NSUN2 stimulated GPX4 mRNA stability and GPX4 expression through enhancing the m5C modification of GPX4 mRNA at coding sequence (CDS). Moreover, NCAPG promoted GPX4 expression in a NSUN2-dependent manner, which also promoted resistance to ferroptosis in HCC. Collectively, the current study identified NCAPG protected HCC cells from undergoing ferroptosis, emphasizing NCAPG as an optional target for potentially developing anti-cancer therapy and improving the effects of ferroptosis in HCC treatment.