Abstract
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.
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Data availability
The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. Full-length western blots are provided as supplementary material file.
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Acknowledgements
The authors would like to thank the Gene Expression and Oncogenesis team for helpful discussions and technical and administrative support (Anne-Gaëlle Rio), CNRS UMR6290, and Rennes FHU CAMIn team. The authors acknowledge the SFR Biosit core facilities of Rennes University, along with the Histo pathology High precision (H2P2, BIOSIT, Biogenouest), member of the national infrastructure France-BioImaging supported by the French National Research Agency (ANR-24-INBS-0005 FBI BIOGEN); the Cell Imaging ImPACcell, Cytometry, Microscopy Rennes Imaging Center (MRIC), and FAIIA Core Facility, from UAR Biosit, Rennes. This study was financially supported by the following: Association Contre le Cancer (ARC); Ligue Nationale Contre le Cancer (LNCC), Départements du Grand-Ouest; FHU CAMIn-CHU Rennes, Région Bretagne; University of Rennes 1; CNRS; and Inserm. C.B. was a recipient of an FHU CAMIn doctoral fellowship.
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CB, HLM, DS, and JG were responsible for conducting the search, extracting, and analyzing data. AS was responsible for designing, performing and analyzing microscopic analysis. EL was responsible for performing in vivo experiment in mouse models. SC contributed to the design of the review protocol, writing the report, arbitrating potentially eligible studies, extracting and analyzing data, and interpreting results. MDG provided feedback on the report.
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Berra, C., Leclair, H.M., Sebillot, A. et al. AhR-dependent ferroptosis as a therapeutic opportunity to counteract BRAFi-resistance in melanoma. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03057-3
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DOI: https://doi.org/10.1038/s41420-026-03057-3
