Yang Ronghui, Guo Zihao, Li Binghui
Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
Trends Cell Biol. 2025 Aug 5. doi: 10.1016/j.tcb.2025.07.005.
Cellular metabolism is intricately regulated by redox signaling, with the NADH/NAD couple serving as a central hub. Emerging evidence reveals that NADH reductive stress, marked by NADH accumulation, is not merely a passive byproduct of metabolic dysfunction but an active regulatory signal driving metabolic reprogramming. In this Review, we synthesize recent advances in understanding NADH reductive stress, including its origins, regulatory mechanism, and manipulation. We examine its broad impact on cellular metabolism, its interplay with oxidative and energy stress, and its pathogenic roles in a range of diseases. By integrating these findings, we propose NADH reductive stress as a master regulator for metabolic reprogramming and highlight new avenues for mechanistic exploration and therapeutic intervention.
