Elesclomol-mediated cuproptosis overcomes cisplatin resistance by restricting epigenetically activated mitochondrial respiration: Novel therapeutic insights into cisplatin-elesclomol combination therapy.

Chemoresistance remains a significant challenge in cancer treatment, substantially limiting therapeutic efficacy. Cuproptosis is copper-induced cell death driven by mitochondrial protein aggregation and metabolic dysfunction. However, the involvement of cuproptosis in chemoresistance remains enigmatic. This study reveals that epigenetic remodeling augments mitochondrial respiration, thereby sensitizing cells to elesclomol-induced cuproptosis in cisplatin-resistant uveal melanoma (UM). First, we established cisplatin-resistant UM cell lines, which were validated in vitro and in vivo. A multi-omics analysis, including transcriptomics, metabolomics, and histone acetylation profiling (H3K9Ac/H3K27Ac CUT&Tag), revealed an upregulation of mitochondrial respiration and downregulation of glycolysis in cisplatin-resistant cells due to changes in histone acetylation. This metabolic reprogramming was associated with increased sensitivity to elesclomol-mediated cuproptosis, characterized by the diminishment of Fe-S cluster proteins and DLAT aggregation. Our research further delineated that the absence of FDX1 not only mitigated the sensitivity of chemoresistant UM cells to elesclomol but also attenuated copper-induced cell death, thereby substantiating the pivotal role of cuproptosis in this context. Therapeutically, employing zebrafish models, orthotopic xenografts, and patient-derived xenografts (PDXs), we confirmed the therapeutic efficacy of elesclomol in overcoming chemoresistance. Collectively, our study highlights a novel avenue for the development of a combinatorial therapeutic approach employing cisplatin and elesclomol to improve chemotherapy outcomes.