Hsa_circ_0003176: a key player in the m6A modification-mediated regulation of autophagy and glycolysis in cisplatin-resistant non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality worldwide, with poor prognosis largely attributed to late-stage diagnosis and therapeutic resistance. Cisplatin (DDP) resistance is a major challenge in NSCLC treatment. Emerging evidence highlights the critical role of N6-methyladenosine (m6A) RNA modification in regulating cancer progression and drug resistance, with methyltransferase-like 3 (METTL3) serving as the key methyltransferase mediating m6A deposition on RNAs. In this study, we investigated the role of the circular RNA hsa_circ_0003176 in DDP-resistant NSCLC and its regulation by m6A modification. We found that hsa_circ_0003176 was significantly downregulated in DDP-resistant NSCLC cells and functioned as a tumor suppressor by promoting autophagy, inhibiting glycolysis, and reversing DDP resistance. Mechanistically, METTL3-mediated m6A modification suppressed hsa_circ_0003176 expression, while hsa_circ_0003176 directly targeted and destabilized ribosomal protein S6 kinase B1 (RPS6KB1) mRNA, a key regulator of mTORC1 signaling, thereby inhibiting NSCLC progression. In addition, in vivo xenograft models confirmed that hsa_circ_0003176 overexpression suppressed tumor growth and enhanced DDP sensitivity. Our study reveals the METTL3/m6A/hsa_circ_0003176/RPS6KB1 pathway as a critical pathway in NSCLC chemoresistance, offering novel therapeutic targets for overcoming DDP resistance.