NSD1-Mediated PPARγ Methylation Enhances PTEN Activity to Suppress Glycolysis and Tumor Progression in Endometrial Cancer

Metabolic reprogramming is a defining feature of endometrial cancer (EC). The upstream molecular mechanisms driving altered metabolism in EC represent potential therapeutic targets. Here, we identified the lysine methyltransferase NSD1-frequently mutated in EC-as a key epigenetic regulator of tumor metabolism. NSD1 directly monomethylated PPARγ at lysine 98 (K98), which enhanced the nuclear localization of PPARγ and promoted transcriptional activation of the tumor suppressor gene PTEN. The resulting elevated PTEN levels led to reduced glycolytic metabolism, cellular proliferation, and invasive potential in EC cells. Loss-of-function mutations in NSD1 abolished PPARγ K98 methylation, resulting in its cytoplasmic retention and impaired PTEN transcription. The consequent depletion of PTEN amplified glycolysis and drove tumor progression. Remarkably, restoration of PTEN expression or pharmacological inhibition of AKT effectively reversed the heightened glycolytic activity and malignant phenotype associated with NSD1 deficiency. Together, these findings reveal a critical epigenetic-metabolic axis in EC, wherein NSD1-mediated methylation of PPARγ at K98 orchestrates tumor-suppressive metabolic control via PTEN. These insights not only elucidate a regulatory pathway in EC pathogenesis but also highlight potential therapeutic targets for intervention in metabolically driven tumors.