Ruxolitinib as a novel therapeutic agent targeting mitochondrial function and chemo-resistance in nasopharyngeal carcinoma.

Chemo-resistance poses a significant obstacle in the effective treatment of nasopharyngeal carcinoma (NPC). To identify novel therapeutic strategies, we conducted high-throughput drug screening using a kinase-focused compound library on chemo-resistant NPC cells and normal human nasopharyngeal epithelial cells (HNECs). The screen identified several compounds with known anti-NPC activities, validating the robustness of the approach, and highlighted ruxolitinib, a Janus kinase (JAK) inhibitor, as a novel candidate. Ruxolitinib demonstrated selective cytotoxicity against NPC cells and exhibited strong synergy with 5-FU and cisplatin, significantly enhancing cytotoxicity in chemo-resistant cell lines. Mechanistic studies revealed that ruxolitinib disrupted mitochondrial bioenergetics through selectively inhibiting complex I activity, leading to reduced oxygen consumption rates, ATP production, and cell viability. In a chemo-resistant NPC mouse model, ruxolitinib delayed tumor growth, reduced tumor cell proliferation as indicated by decreased Ki67 staining, and extended overall survival without affecting body weight, demonstrating its efficacy and safety in vivo. These findings position ruxolitinib as a promising therapeutic agent for overcoming chemo-resistance in NPC, warranting further investigation into its clinical potential.