Enhancing the therapeutic efficacy of gambogenic acid by modulating the NRF2/HSF1/HO-1 signaling pathway in cisplatin-resistant lung cancer cells

Subsequent analyses indicated that GNA treatment elicited a heat-shock response, particularly in cells with NRF2 knockdown. While baseline HO-1 expression in A549/DDP cells is regulated by NRF2, the upregulation of HO-1 induced by GNA is dependent on HSF1, a key regulator of the heat-shock response. Furthermore, although treating cells with HO-1 inhibitors alone did not affect the viability of A549/DDP cells, it dramatically enhanced the GNA-induced cell death in combinational therapy.

Collectively, our findings demonstrated that GNA possesses substantial cytotoxic activity in cisplatin-resistant lung cancer cells, and the effect can be augmented by disrupting the NRF2 and HSF1 signaling pathways, which jointly promote HO-1 expression in cells coping with GNA-induced acute stress. This study underscores a novel mechanism underlying the anticancer activity of GNA and suggests a potential strategy to overcome the translational challenges of GNA in lung cancer therapy.