Targeting aldehyde dehydrogenase in hepatocellular carcinoma: mechanistic insights and therapeutic advances

Abstract:

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with poor prognosis, closely linked to oxidative stress, metabolic reprogramming, and tumor microenvironment alterations. Aldehyde dehydrogenase (ALDH) plays multifaceted roles in HCC by regulating oxidative stress, modulating glucose and lipid metabolism, sustaining cancer stem cell properties, and promoting immune evasion, making it a promising therapeutic target. This review summarizes the expression patterns and mechanistic functions of ALDH in HCC, highlights advances in ALDH-targeted therapies, including inhibitors such as disulfiram and diethylaminobenzaldehyde, and ALDH-based peptide vaccines-and discusses their potential in combination with immunotherapy and chemotherapy. Current evidence suggests that ALDH inhibition can suppress tumor growth, reverse drug resistance, and enhance antitumor immunity. Future research should aim to improve drug selectivity and safety, and to develop personalized combination strategies to optimize clinical outcomes in HCC patients.