UFSP2 suppresses UFMylation of NONO to govern glycolysis in hepatocellular carcinoma.

Metabolic reprogramming serves as a driving factor of hepatocellular carcinoma (HCC). However, the key signaling pathway of metabolic reprogramming driving HCC remain to be elucidated. In this study, we found that the deUFMylase UFSP2 is notably upregulated and predicts unfavorable prognosis in HCC. In addition, UFSP2 exerts potent pro-tumorigenic and pro-metastatic effects on HCC cells. Transcriptomic and metabolomic results revealed that silencing UFSP2 substantially decreases the levels of glycolysis and its associated gene transcripts. Mechanistically, UFSP2 physically associates with the glycolytic regulator NONO. This interaction mediates NONO de-UFMylation, which in turn impedes ubiquitination-mediated proteolysis and ultimately sustains NONO protein abundance. UFSP2 silence reduces the expression of NONO down-stream glycolytic targets (such as Glut1, LDHA, and ZEB1). Furthermore, rescue experiments showed that overexpression of NONO significantly restores the suppression of growth, invasion, and glycolysis induced by UFSP2 deficiency in HCC cells and mouse model. Importantly, the positive correlation was confirmed among UFSP2, NONO, ZEB1, Glut1 and LDHA in clinical HCC samples. Overall, our findings uncover the UFSP2-NONO axis as a key mediator of the glucose metabolism and malignant progression in HCC, providing a potential strategy for HCC treatment.