AhR-dependent ferroptosis as a therapeutic opportunity to counteract BRAFi-resistance in melanoma.

Drug resistance limits the achievement of persistent cures for the treatment of melanoma, despite the efficacy of targeted therapies. This study explored how transcriptional regulation governs metabolic adaptations that underlie resistance. Our analysis of the metabolic profiles revealed a distinct shift in resistant melanoma cells-from glycolytic metabolism in BRAFi-sensitive cells to oxidative phosphorylation (OXPHOS) dependence. This transition was accompanied by a reprogramming of transcriptional networks, marked by the downregulation of MITF transcription factor and a pronounced upregulation and activation of the Aryl hydrocarbon Receptor (AhR). AhR emerged as a key regulator of this resistant phenotype, contributing to the metabolic switch that enhances mitochondrial function, elevates reactive oxygen species (ROS) production, and drives lipid peroxidation. This reprogramming sensitizes resistant cells to ferroptosis, a regulated cell death driven by iron-dependent lipid peroxidation. Importantly, pharmacological activation or stabilization of AhR exacerbated this susceptibility, while its inhibition mitigated ferroptotic responses-highlighting AhR not only as a mediator of resistance-associated metabolic rewiring but also as a potential therapeutic target. Collectively, these findings position AhR as a central node linking metabolic plasticity to ferroptosis vulnerability, offering a novel axis for therapeutic intervention in drug-resistant melanoma.