Irisin regulates lipid metabolism and ferroptosis in ovarian cancer cells by modulating the ALOX5-5-HETE-PD-L1 axis.

This study investigates the role of arachidonate 5-lipoxygenase (ALOX5) in upregulating programmed death-ligand 1 (PD-L1) expression via its metabolite 5-hydroxyeicosatetraenoic acid (5-HETE) in ovarian cancer cells, and explores the effects on lipid metabolism and ferroptosis. Additionally, the study examines the role of Tectorigenin (TEC) in this process. Using network pharmacology, bioinformatics analysis, molecular docking, and drug affinity reaction target stability (DARTS) experiments, we identified ALOX5 as a potential therapeutic target for TEC in ovarian cancer treatment, possibly through lipid metabolism and ferroptosis pathways. In vitro experiments showed that TEC inhibits proliferation and invasion and promotes apoptosis in ovarian cancer cells without significant cytotoxicity in normal ovarian epithelial cells. TEC also inhibits lipid metabolism and promotes ferroptosis, reducing ovarian cancer cell viability. Inhibition of ALOX5 similarly suppresses lipid metabolism and enhances ferroptosis, effects that can be reversed by exogenous 5-HETE. In vivo studies using a nude mouse model demonstrated that TEC inhibits tumor growth and downregulates ALOX5, 5-HETE, and PD-L1 expression in tumor tissues. The findings suggest that the ALOX5/5-HETE signaling pathway is crucial for regulating lipid metabolism and ferroptosis in ovarian cancer, and TEC may exert its anti-tumor effects, at least in part, by modulating this pathway (The graphical abstract was shown in Fig. 1).