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. During stress, Sesn2 activates AMPK, which inhibits mTORC1. This is important for autophagy because halts its inhibition of ULK1. ULK1 initiates production of PI3P. PI3P is formed from the phosphorylation of PI from the PI3K complex. This complex is composed of Beclin1, VPS34, and ATG14. Sesn2 can target beclin1 in particular to enhance its ability to form the autophagosome. PI3P, WIPI, and DFCP1 initiate the autophagosome for elongation. ATG and LC3‐II are then recruited for further elongation. Sesn2 helps the recruitment of Parkin to damaged mitochondria to be tagged. SQSTM1 then collects tagged misfolded or damaged proteins and mitochondria to bring to LC3‐II. Snare proteins then help bring the autophagosome to the lysosome so that its contents can be degraded. Created with Biorender.com.