Regulation of SLC7A11 by METTL3 induces cisplatin resistance in esophageal cancer.

Cisplatin resistance remains a significant obstacle in the treatment of esophageal squamous cell carcinoma (ESCC), yet its underlying molecular mechanisms are incompletely understood. This study examined whether METTL3-mediated m6A methylation and YTHDF2 SUMOylation collaboratively modulate SLC7A11 expression to drive cisplatin resistance in ESCC. Using cisplatin-resistant ESCC cell lines, clinical tissue samples, in vivo xenograft models, and functional assays, including CCK-8, ROS/GSH/MDA detection, RNA immunoprecipitation (RIP), MeRIP-qPCR, and SUMOylation analyses, we demonstrate that METTL3 exerts opposing, context-dependent effects on SLC7A11 mRNA stability. In cisplatin-sensitive cells, METTL3-mediated m6A modification promotes YTHDF2 binding to SLC7A11 mRNA, leading to its degradation and enhanced oxidative stress. In resistant cells, however, upregulation of the SUMO-specific protease Senp1 triggers YTHDF2 deSUMOylation, reducing its RNA-binding affinity and allowing YTHDF1 to instead stabilize SLC7A11 transcripts. This shift results in elevated SLC7A11 expression, enhanced antioxidant capacity, and cisplatin resistance. Importantly, restoring YTHDF2 SUMOylation via Senp1 knockdown reversed SLC7A11 overexpression and resensitized resistant cells to cisplatin both in vitro and in vivo. These findings reveal a SUMOylation-dependent switch in m6A reader function as a novel mechanism underlying chemoresistance, reconciling previously conflicting reports on the role of METTL3 in SLC7A11 regulation, and identify the METTL3-YTHDF1/2-SLC7A11 axis, particularly the Senp1-YTHDF2 node, as a potential target warranting further investigation for overcoming cisplatin resistance in ESCC.