Citronellol potentiates sunitinib efficacy in renal cell carcinoma by targeting JAK2/STAT3 signaling pathway.

Renal cell carcinoma. (RCC) is the most common form of kidney cancer and frequently develops resistance to tyrosine kinase inhibitors (TKIs), such as sunitinib, limiting treatment efficacy. To address this challenge, we investigated the potential of Citronellol, a plant-derived monoterpenoid, to enhance sunitinib sensitivity in RCC. Through network pharmacology analysis, the potential targets of Citronellol were identified, and it was confirmed that it may exert anticancer effects through the EGFR and JAK2/STAT3 signaling pathways. In vitro experimental results showed that Citronellol significantly inhibited the proliferation and migration of 786-O and A498 cells and induced apoptosis. Furthermore, when combined with sunitinib treatment, Citronellol significantly reduced the IC50 value of sunitinib and enhanced its inhibitory effect on renal cancer cells. Western blot results further revealed that Citronellol significantly inhibited the phosphorylation of EGFR, JAK2, and STAT3, suggesting that it may enhance the anticancer activity of sunitinib by inhibiting the survival signals mediated by the JAK2/STAT3 signaling pathway. This study is the first to systematically reveal that Citronellol enhances the therapeutic effect of sunitinib in RCC cells by modulating the JAK2/STAT3 signaling pathways. These findings suggest a promising combination strategy for overcoming TKI resistance and improving RCC treatment outcomes.