Abstract

Chemoresistance remains a major therapeutic challenge in gastric cancer (GC). We report that the long non-coding RNA (lncRNA) Linc00347 is markedly upregulated in oxaliplatin (Oxa)-resistant GC tissues relative to Oxa-sensitive counterparts, and its elevated expression correlates with poor patient prognosis. Functionally, Linc00347 conferred Oxa resistance and accelerated tumor growth in vivo by repressing ferroptosis. Mechanistically, Linc00347 directly interacted with the RNA-binding protein YBX1 and prevented its proteasomal degradation by recruiting the deubiquitinase USP10. The stabilized YBX1 then served as an m5C 'reader' to specifically recognize and bind FoxO6 mRNA m5C-modified by the methyltransferase NSUN2, thereby enhancing FoxO6 mRNA stability. Crucially, FoxO6 depletion restored ferroptosis sensitivity and overturned Linc00347-driven chemoresistance. Our results establish the Linc00347/YBX1/FoxO6 axis as a novel and therapeutically exploitable driver of ferroptosis suppression in GC chemoresistance.