Opportunities and challenges of dihydrodiol dehydrogenase expression in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a prevalent global malignant tumor, which frequently exhibits a concomitant dysregulation of redox homeostasis and energy metabolism. TP53, a core tumor suppressor gene, can influence HCC progression by regulating mitochondrial homeostasis and ferroptosis. Abnormal Dihydrodiol dehydrogenase（DDH ）expression causes mitochondrial dysfunction, driving HCC malignant transformation and drug resistance. Currently, existing HCC therapeutic approaches have limitations, and advanced HCC patients have a low survival rate. DDH interacts with the TP53-NRF2-AKR pathway and is a potential therapeutic target for HCC with TP53 loss mutations. However, current HCC-targeting drugs can't effectively inhibit DDH, so it's significant to search for DDH inhibitors. In this study, we investigate HCC with TP53 loss mutations to correct mitochondrial dysfunction, dissect drug-resistance mechanisms, and develop targeted therapeutic strategies against DDH.