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BACKGROUND AND OBJECTIVES: Induction of PGC1α/oxidative phosphorylation (OXPHOS) is associated with disease progression and treatment resistance in cutaneous melanoma patients. Loss of the TET2/5-hydroxymethylcytosine (5-hmC) epigenetic pathway is linked to melanoma aggressiveness, although the underlying mechanisms remain unclear. Here we explored a relationship between TET2-mediated DNA hydroxymethylation and the induction of PGC1α/OXPHOS in melanoma.METHODS: RNA-sequencing data from 368 melanoma metastases (MMs) and 102 melanoma primaries (MPs) were analyzed, with tumors categorized as "TET2-low" and "TET2-high" based on gene expression. Differential gene expression and gene set enrichment analyses were conducted, with further validation using a tissue microarray (TMA) comprised of 33 clinical specimens and a publicly available gene expression dataset from 209 melanoma primaries. Confirmatory in vitro and in vivo studies were performed using melanoma cell lines with altered TET2 and PGC1α expression. 5-hmC and 5-mC levels at the PGC1α gene were assessed using hydroxymethylated and methylated DNA immunoprecipitation sequencing (hMeDIP-seq and MeDIP-seq).RESULTS: PGC1α/OXPHOS was significantly upregulated in TET2-low MMs and MPs. TMA analysis and gene expression studies showed an inverse relationship between TET2/5-hmC and PGC1α/OXPHOS expression. In vitro and in vivo, PGC1α/OXPHOS was higher in TET2-low cells. hMeDIP-seq identified significantly lower 5-hmC levels at an upstream PGC1α active enhancer in melanomas vs. nevi, in TET2-low vs. TET2-high cells, and in cells expressing catalytically inactive TET2 vs. cells expressing wild-type TET2. Inhibition of PGC1α/OXPHOS mitigated migration and invasion in vitro and metastasis in vivo, and TET2 loss associated with resistance to MAPK pathway inhibition and enhanced sensitivity to OXPHOS inhibition.CONCLUSION: Loss of TET2 promotes activation of PGC1α/OXPHOS in melanoma, thereby driving metabolic reprogramming that supports tumor progression and resistance to MAPK inhibition in a subset of tumors. Importantly, this phenotype renders TET2-deficient melanomas selectively vulnerable to OXPHOS inhibition, identifying an actionable therapeutic opportunity. These findings establish an epigenetic-metabolic axis as a critical determinant of melanoma aggressiveness and highlight TET2/5-hmC as both a potential biomarker and a targetable pathway.