Dual roles and therapeutic potential of ALDH3 family members in cancer

The aldehyde dehydrogenase 3 (ALDH3) family, a group of metabolic enzymes within the ALDH superfamily, plays a critical role in oxidative stress defense and lipid homeostasis by efficiently catalyzing lipid peroxidation products such as 4-HNE. Recent studies have revealed that ALDH3 family members (ALDH3A1, ALDH3A2, ALDH3B1, and ALDH3B2) exhibit functional heterogeneity across different types of tumors. They can act as pro-oncogenic factors by inducing metabolic reprogramming to support the survival of tumor cells, enhance resistance to chemotherapy, or aid in maintaining tumor stemness. Conversely, they may also exert tumor-suppressive effects, such as inducing reductive stress or inhibiting pro-tumorigenic microenvironments. This review systematically summarizes the molecular characteristics, metabolic functions, and dual roles of the ALDH3 family in tumors, while exploring their clinical translational potential. A deeper understanding of the multifaceted biology of ALDH3 will provide new insights into tumor metabolic diversity and guide the development of precision therapeutic strategies.