Multifaceted Stress Induction and Autophagic Flux Disruption by Shikonin Amplify Apoptotic Death in Melanoma Cells.

Melanoma is an aggressive malignancy with high metastatic potential. Although BRAF/MEK inhibitors and immune checkpoint therapies have improved patient outcomes, their efficacy is often constrained by toxicity, resistance, and relapse. Hence, safer multitargeted agents are needed. Shikonin, a naphthoquinone derivative, has shown anticancer activity in several tumor types; here, we delineate its mechanism of action in melanoma. Shikonin selectively induced cytotoxicity in melanoma cells through excessive ROS generation, resulting in mitochondrial depolarization, Bax/Bcl-2 modulation, cytochrome c release, and activation of the caspase-9/PARP apoptotic cascade. Elevated ROS triggered ER stress via eIF2α phosphorylation and ATF4–CHOP activation, subsequently suppressing autophagic flux through Beclin-1 downregulation, p62 accumulation, and lysosomal destabilization. ROS scavenging abolished these effects, confirming redox dependency. In melanoma xenografts, Shikonin markedly inhibited tumor growth without systemic toxicity. These findings identify Shikonin may represent a redox-active, autophagy-modulating phytochemical with potential translational value in melanoma, although further studies are needed to fully validate its therapeutic utility.