Biochem Pharmacol. 2025 Aug 28;242(Pt 1):117287
Flubendazole inhibits cervical carcinoma by targeting DHODH to induce ferroptosis and mitophagy
Abstract
Cervical carcinoma remains a major public health challenge due to its elevated incidence and mortality rates. Dihydroorotate dehydrogenase (DHODH) is a crucial enzyme in de novo pyrimidine biosynthesis and ferroptosis defense with a targetable susceptibility in cancer. However, effective inhibitors of DHODH and their potential application in cervical cancer therapy have not yet been explored. This study aims to evaluate the inhibitory effects of flubendazole, a benzimidazole anthelmintic, on cervical carcinoma and the mechanisms involved. This study demonstrated that flubendazole effectively inhibited cervical cancer cell proliferation and tumor growth by inducing ferroptosis and PINK1/Parkin-mediated mitophagy. Mechanistically, flubendazole targeted DHODH and promoted its degradation via direct binding. Overexpression of DHODH prevented flubendazole-induced ferroptosis and mitophagy and markedly attenuated its anti-cancer effects in cervical cancer cells. Additionally, flubendazole enhanced the sensitivity of cervical cancer cells to ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition and showed a potent synergistic anti-tumor effect in combination with GPX4 inhibitor in xenograft mouse models. These findings highlight the promising potential of flubendazole as a repurposed drug for cervical cancer therapy by inducing ferroptosis through inhibition of DHODH.
Products: PHF91801, Anti-DHODH Polyclonal Antibody
