Ononin suppresses thyroid cancer cell proliferation and induces apoptosis by inhibiting NSUN6-mediated m5C methylation of SKP2

Aim This study investigated the anti-tumor efficacy of ononin in thyroid cancer (TC) and its molecular mechanisms.Methods In vitro, TPC-1 and IHH-4 cells treated with ononin were assessed for proliferation, apoptosis, global m5C levels, and the NSUN6–SKP2 interaction. A xenograft mouse model was used for in vivo validation.Results Ononin suppressed TC cell proliferation, induced apoptosis, and reduced NSUN6-mediated m5C modification. Mechanistically, NSUN6 directly bound SKP2 mRNA and deposited m5C at site 2576, enhancing its stability. Overexpression of NSUN6 or SKP2 reversed ononin’s anti-tumor effects. In vivo, ononin inhibited tumor growth without significant toxicity to normal thyroid epithelial cells or major mouse organs.Conclusion Ononin exerts anti-TC activity via the NSUN6/SKP2 axis, identifying NSUN6 as a potential therapeutic target and ononin as a candidate compound for TC worthy of further clinical investigation.