The ubiquitin ligase LONRF2 inhibits glycolysis and malignant phenotypes in endometrial cancer through aldolase a degradation.

The pathogenesis of endometrial cancer (EC) remains poorly understood. This study aimed to delineate the expression profile of LON peptidase N-terminal domain and ring finger 2 (LONRF2) in EC and to elucidate its mechanistic role in modulating the proliferative, metabolic, and invasive capacities of EC cells. LONRF2 expression was analyzed in EC tissues and cell lines. EC cells overexpressing LONRF2 were evaluated for malignant phenotypes. Aldolase A (ALDOA) was identified as a LONRF2-interacting protein via immunoprecipitation and nano-liquid chromatography-tandem mass spectrometry. Their regulatory relationship was examined by assessing ALDOA stability and ubiquitination. Functional exploration of the LONRF2/ALDOA axis involved combined LONRF2 knockdown, ALDOA knockdown, ALDOA knockout, or treatment with the ALDOA inhibitor itaconate in EC cells to assess malignant phenotypes, along with a xenograft model to evaluate tumor growth. LONRF2 was downregulated in clinical EC tissue and cell lines. LONRF2 overexpression inhibited the growth, glycolysis, migration, and invasion of KLE cells. LONRF2 interacted with ALDOA and induced its ubiquitination and degradation. In line with this mechanism, the enhanced malignant phenotypes caused by LONRF2 silencing were reversed by either knocking down ALDOA or administering itaconate. ALDOA-knockout cells confirmed that itaconate suppresses EC cell growth, glycolysis, migration, and invasion by targeting ALDOA. Consistently, itaconate abolished the tumor-promoting effect of LONRF2 silencing in a xenograft model. This study identifies the LONRF2/ALDOA axis as a key driver of EC progression, primarily by regulating glycolysis. Targeting this axis, particularly LONRF2, presents a promising therapeutic strategy for EC.