Ciclopirox suppresses melanoma growth by activating ER stress-driven apoptosis and disrupting Src/STAT3 signaling

Ciclopirox (CPX), an FDA-approved Antifungal drug, exhibits promising antitumor activity. This study investigates its efficacy and mechanisms against melanoma. Here, we find that CPX potently inhibits melanoma cell proliferation, migration, and invasion in vitro and significantly suppresses xenograft tumor growth in vivo (20 mg/kg body weight, i.p.). Mechanistically, CPX induces mitochondrial dysfunction and a Reactive Oxygen Species burst, activating PERK-dependent endoplasmic reticulum stress and ultimately triggering Apoptosis via Caspase-3 activation. This apoptotic process is rescued by the antioxidant N-acetylcysteine, supporting a causative role of oxidative stress in CPX-induced cytotoxicity. Furthermore, CPX directly binds to the Src kinase domain, inhibiting its autophosphorylation and subsequently mediating a concentration-dependent reduction in STAT3 phosphorylation at Tyr705. It also downregulates total STAT3 protein levels and Ser727 phosphorylation, indicating multi-level disruption of STAT3 signaling. In conclusion, our findings reveal that CPX suppresses melanoma through dual mechanisms: activating ROS/ER stress-mediated Apoptosis and disrupting the Src/STAT3 signaling pathway, supporting its therapeutic repurposing for melanoma.