SENP1 drives de novo cholesterogenesis via disrupting SUMOylation-mediated SREBP2-FBXW7 interaction

Aberrant cholesterol accumulation in diverse cancers is associated with intratumoral hypoxia, whereas the specific mechanistic connection underlying hypoxia-driven cholesterol metabolic dysregulation in prostate cancer (PCa) remains undefined. Our previous findings indicate that the positive feedback loop involving SUMO-specific protease 1 (SENP1) and hypoxia-inducible factor-1α (HIF-1α) is critical to maintaining hypoxia-mediated metabolic reprogramming, while whether SENP1 modulates hypoxia-driven cholesterol metabolism remains unclear. Correlations among SENP1 expression, hypoxic status, and cholesterol metabolic profiles were analyzed using TCGA/GEO datasets, PCa tissue microarrays, and PCa cell lines. A series of molecular biology approaches, including co-immunoprecipitation, SUMOylation assay, proximity ligation assay (PLA), Western blotting, and luciferase reporter assay, were performed in HEK293T and PCa cells to clarify the regulatory mechanism of SENP1 in cholesterol metabolism. Patient-derived organoids (PDOs) and xenograft mouse models were utilized to evaluate the anti-tumor efficacy and safety of the SENP1 inhibitor Momordin Ic in vitro and in vivo. SENP1 expression was positively correlated with the expression of key cholesterogenic enzymes in PCa, and SENP1 was essential for hypoxia-induced intracellular cholesterol accumulation. Mechanistically, SENP1 directly catalyzed the deSUMOylation of sterol regulatory element-binding protein 2 (SREBP2) at the lysine 464 (K464) residue, which disrupted the interaction between SREBP2 and the E3 ubiquitin ligase FBXW7 and thereby stabilized the SREBP2 protein. Therapeutically, targeted inhibition of SENP1 by Momordin Ic significantly suppressed de novo cholesterogenesis, impaired the viability of PCa PDOs, and robustly inhibited tumor growth in xenograft models without inducing obvious systemic toxicity. Our study uncovers a previously unrecognized SENP1–SREBP2 regulatory axis that mediates hypoxia-induced de novo cholesterol biosynthesis in PCa, and identifies SENP1 as a promising therapeutic target for metabolic intervention in PCa treatment.