Dual ferroptosis suppressor protein 1-coenzyme Q10 and dihydroorotate dehydrogenase pathways in ferroptosis of hepatocellular carcinoma： Mechanisms and its clinical significance

Hepatocellular carcinoma （HCC） is a common malignant tumor with a high fatality rate worldwide， with limited overall survival benefits and pronounced drug resistance issues， highlighting the urgent need for novel sensitization strategies and patient stratification systems. Ferroptosis， as an iron-dependent form of lipid peroxidation-driven cell death， is closely associated with tumor treatment responses. In addition to the classic glutathione peroxidase 4 （GPX4）/glutathione （GSH） pathway， the ferroptosis suppressor protein 1 （FSP1）-coenzyme Q10 （CoQ10） pathways and the dihydroorotate dehydrogenase （DHODH） pathway are two newly identified anti-ferroptosis pathways that function at the plasma membrane and mitochondria， respectively， and determine cellular sensitivity to ferroptosis in synergy with GPX4. This article systematically reviews the mechanism of action of the FSP1-CoQ10 and DHODH pathways in HCC and related research advances， proposes related therapeutic strategies， and look forward to its clinical translation and application prospects.