Geniposide enhances cisplatin sensitivity in non-small cell lung cancer through PUMA-mediated apoptotic pathway.

[BACKGROUND] Cisplatin-based chemotherapy remains the standard treatment for advanced non-small cell lung cancer (NSCLC); however, its efficacy is constrained by acquired drug resistance and dose-limiting toxicity. Dysregulated apoptosis is recognized as a key mechanism contributing to cisplatin resistance in NSCLC. Geniposide, an active component of traditional Chinese medicine, has demonstrated broad-spectrum antitumor activity; however, its role in cisplatin resistance remains unclear.

[METHODS] Network pharmacology was employed to identify potential targets. The platinum-resistant A549/DDP cell line and its parental A549 line were used as in vitro models. Functional assays were performed to evaluate proliferation, apoptosis, migration, and mitochondrial membrane potential. RNA sequencing and gene knockdown/overexpression approaches were performed to investigate the underlying molecular mechanisms. An A549/DDP xenograft model was used to assess in vivo therapeutic efficacy.

[RESULTS] Network pharmacology analysis identified 125 common targets enriched in apoptosis and p53 signaling pathways. Geniposide significantly enhanced cisplatin sensitivity in A549/DDP cells by inhibiting proliferation and migration while promoting apoptosis and inducing mitochondrial membrane potential dissipation. RNA-seq identified PUMA as a key pro-apoptotic mediator. Combined treatment markedly upregulated PUMA expression, accompanied by activation of p53 signaling. Silencing of PUMA or p53 attenuated the chemosensitizing and pro-apoptotic effects, whereas PUMA overexpression independently reduced cisplatin IC₅₀ values. In vivo, geniposide combined with low-dose cisplatin achieved tumor suppression comparable to high-dose cisplatin without inducing systemic toxicity.

[CONCLUSION] These findings demonstrate that geniposide enhances cisplatin sensitivity in NSCLC by activating the p53-PUMA-mediated mitochondrial apoptotic pathway, thereby providing a potential strategy for overcoming chemotherapy resistance with improved safety.