Sestrin2 serves as a scaffold protein to maintain cardiac energy and metabolic homeostasis during pathological stress.

Cardiovascular diseases (CVDs) are a leading cause of morbidity and mortality worldwide. Metabolic imbalances and pathological stress often contribute to increased mortality. Sestrin2 (Sesn2) is a stress-inducible protein crucial in maintaining cardiac energy and metabolic homeostasis under pathological conditions. Sesn2 is upregulated in response to various stressors, including oxidative stress, hypoxia, and energy depletion, and mediates multiple cellular pathways to enhance antioxidant defenses, promote autophagy, and inhibit inflammation. This review explores the mechanisms through which Sesn2 regulates these pathways, focusing on the AMPK-mTORC1, Sesn2-Nrf2, and HIF1α-Sesn2 pathways, among others. We can identify the potential therapeutic targets for treating CVDs and related metabolic disorders by comprehending these complex mechanisms. Sesn2's unique ability to respond thoroughly to metabolic challenges, oxidative stress, and inflammation makes it a promising prospect for enhancing cardiac health and resilience against pathological stress.