Drug resistance remains a major obstacle to effective lung cancer treatment. Cisplatin, which is a platinum-based chemotherapeutic agent, is widely used as a first-line treatment for non-small cell lung cancer (NSCLC); however, its clinical efficacy is often limited by the development of resistance. MicroRNAs (miRNAs) are key regulators of the epigenetic landscape and have been reported to play critical roles in various cancer-related processes. This study aimed to identify potential miRNAs associated with the DNA damage response (DDR), which is a major mechanism underlying cisplatin sensitivity, and to investigate the role of miRNAs in modulating the cisplatin response.

Differential expression analysis of DNA damage response-related miRNAs was performed using lung cancer datasets from The Cancer Genome Atlas (TCGA). The role of miR-145-5p in cisplatin responsiveness was evaluated by transfecting lung cancer cell lines with a miR-145-5p mimic. The IC₅₀ of cisplatin was assessed using the MTT assay. Cisplatin-induced apoptosis was investigated through apoptosis assays. In addition, changes in apoptosis markers and associated signaling pathways were analyzed by immunoblotting. The potential target of miR-145-5p was identified by integrating data from multiple miRNA databases. The regulatory relationship between miR-145-5p and its target in relation to cisplatin sensitivity was further validated using luciferase reporter assays, RNA interference, and rescue experiments.

miR-145-5p was identified as a strong candidate, as it was observed to significantly downregulated in lung tumor tissues and associated with poor prognosis. In vitro experiments demonstrated that miR-145-5p expression was positively correlated with cisplatin sensitivity across a panel of NSCLC cell lines and that its overexpression reduced the cisplatin IC₅₀ while increasing apoptosis. By integrating target prediction and validation by a luciferase reporter assay, CAMSAP2 was identified as a potential direct target of miR-145-5p. CAMSAP2 expression was negatively associated with cisplatin responsiveness, and rescue experiments confirmed that miR-145-5p could enhance cisplatin-induced apoptosis by downregulating CAMSAP2.

miR-145-5p directly targets and suppresses CAMSAP2, sensitizing lung cancer cells to cisplatin. These findings highlight the miR-145-5p/CAMSAP2 regulatory axis as a critical modulator of cisplatin sensitivity and a potential therapeutic target for overcoming drug resistance in lung cancer.