A Metabolic‐Epigenetic Axis of AARS1/IGF2BP3‐K280 Lactylation Sustains Endometrial Cancer Stemness and Recurrence

Abstract

ABSTRACT Endometrial cancer (EC) recurrence is strongly associated with enhanced tumor stemness. While lactate—a major tumor‐derived metabolite—is known to promote immunosuppression across cancers, its contribution to EC stemness and recurrence remains poorly understood. In this study, we show that elevated protein lactylation in EC correlates with heightened tumor stemness and unfavorable prognosis. Mechanistically, a lactate‐enriched microenvironment induces lactylation of insulin‐like growth factor 2 mRNA‐binding protein 3 (IGF2BP3), thereby stabilizing and upregulating the protein. This modification enhances EC stemness by enabling IGF2BP3 to stabilize HMGA2 mRNA via an m6A‐dependent pathway, activating downstream stemness‐related transcriptional programs. This effect requires lysine 280 (K280) lactylation mediated by alanyl‐tRNA synthetase 1 (AARS1), as either AARS1 depletion or IGF2BP3‐K280 mutation abolishes lactylation and attenuates stemness. Both genetic and pharmacologic inhibition of IGF2BP3 lactylation markedly suppress tumor growth and stem‐like properties in vitro and in vivo. Clinically, IGF2BP3‐K280 lactylation correlates with aggressive clinicopathological features and poor survival, outperforming conventional biomarkers in recurrence prediction. Integration of IGF2BP3‐K280 lactylation into a clinical nomogram substantially improved recurrence‐risk stratification across multi‐center cohorts. Collectively, these findings uncover a metabolic–epigenetic mechanism linking lactate metabolism to m6A‐mediated stemness regulation, establishing IGF2BP3‐K280 lactylation as both a therapeutic vulnerability and a precision biomarker for EC recurrence.