Proline metabolism reprogramming in cancer reveals the regulation of PRODH/POX as target

Proline dehydrogenase (PRODH) plays a dual role in cancer by catalyzing the first step of proline catabolism. During tumor metabolic reprogramming, PRODH catalyzes the conversion of proline to Δ¹-pyrroline-5-carboxylate (P5C), which enters the tricarboxylic acid cycle and supports cancer cell growth and energy supply. However, the increased activity of PRODH also generates reactive oxygen species (ROS), which can induce apoptosis or autophagy, potentially inhibiting cancer progression or promoting cancer immune responses. This article analyzes the role of PRODH in various types of cancer and highlights its involvement in immune evasion. Additionally, this article discusses the potential of PRODH as a therapeutic target by providing a comprehensive analysis of current therapeutic strategies, including direct and indirect inhibitors. This framework provides a theoretical basis for precise metabolic therapy and combinatorial approaches to overcome therapeutic resistance. • PRODH converts proline to P5C to fuel the TCA cycle for energy supply. • PRODH-derived ATP supports cancer cell survival under nutrient stress. • Excessive ROS generation by PRODH induces tumor cell apoptosis. • p53 and AMPK signaling pathways upregulate PRODH to regulate cell fate. • Targeting PRODH metabolism overcomes therapeutic resistance in cancer.