Abstract
Background: Circular RNAs (circRNAs) play critical roles in tumorigenesis. However, their function in cisplatin (CDDP) resistance of non-small cell lung cancer (NSCLC) remains incompletely understood. We aimed to investigate the expression pattern of hsa_circ_0135681 in NSCLC and its role in regulating cisplatin resistance. Method: RNA sequencing was performed on serum samples to identify differentially expressed circRNAs (DEcircRNAs) using thresholds of |log2FC| >1 and p < 0.05. We validated candidate DEcircRNAs via quantitative real-time PCR (qRT-PCR) in NSCLC tissues. We conducted functional assays, including CCK-8 proliferation, wound healing assay, and flow cytometry apoptosis analysis. Finally, nude mouse xenograft models were used to investigate the role of circRNA in vivo. In mechanistic investigations, lactate and glucose detection kits were used, with subsequent validation conducted via Western blot (WB) and qRT-PCR. Results: A total of 411 DEcircRNAs were identified in serum samples, and the 9 selected candidate DEcircRNAs were further validated in NSCLC tissues. Among these, hsa_circ_0135681 was significantly downregulated in NSCLC tissues compared to adjacent non-cancerous tissues. Overexpression of hsa_circ_0135681 could inhibit the proliferation and migration of A549/DDP cells, induce apoptosis in vitro, and similarly suppress tumorigenesis in vivo. Mechanistically, hsa_circ_0135681 overexpression reduced glycolytic activity and reversed EMT in A549/DDP cells. Additionally, bioinformatics analysis predicted two potential regulatory axes: hsa_circ_0135681/hsa-miR-4299/RNF180 and hsa_circ_0135681/hsa-miR-4299/SOCS5. Conclusion: Collectively, hsa_circ_0135681 is a tumor-suppressive circRNA that modulates glycolysis and EMT. These findings may provide a potential therapeutic target for cisplatin-resistant NSCLC. Supplementary Information: The online version contains supplementary material available at 10.1007/s12672-025-04024-7.