Sesn2, also known as Sestrin2, is a stress-inducible protein and a powerful anti-oxidant [1]. It is transcriptionally activated by stress factors like metabolic derangements, reactive oxygen species (ROS), and DNA-damage. One of its well-known functions is the inhibition of the mechanistic target of rapamycin complex 1 kinase (mTORC1), which is crucial for cell growth and autophagy regulation. It also has mTORC1-independent activities related to mitochondrial function and cell death regulation. Sesn2 is involved in multiple biological processes, such as oxidative stress response, cell viability control, and mitochondrial homeostasis, and is thus of great biological importance. Genetic models, like KO/CKO mouse models, can help in further understanding its functions.

In Sesn2-deficient mice, defective mitophagy was observed, leading to hyperactivation of inflammasomes and increased mortality in sepsis models, indicating Sesn2's role in suppressing sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages [3]. In high-fat diet-induced obese mice, obesity decreased Sesn2 expression in adriamycin-exposed hearts. Overexpression of Sesn2 blocked the destructive cascades and cardiac oxidative damage effects induced by high-fat diet/sodium palmitate combined with adriamycin, suggesting it could be a therapeutic target for improving anthracycline-related cardiotoxicity in obesity [2]. In addition, knockdown of Sesn2 in mdx mice, an animal model of Duchenne muscular dystrophy (DMD), led to decreased Myogenin (Myog) expression and increased Pax7 expression, while its overexpression enhanced the proportion of slow-switch myofibers, indicating its role in promoting myogenic differentiation and skeletal muscle regeneration [4]. In genetic defective mice of Sesn2 (Sesn2-/-), dendritic cells (DCs) exhibited exacerbated ferroptosis, suggesting Sesn2 can suppress DC ferroptosis in sepsis by down-regulating the ATF4-CHOP-CHAC1 signaling pathway [5]. Knockdown of Sesn2 in denervated mouse gastrocnemius muscles aggravated atrophy, while Sesn2 induction protected against atrophy through the unfolded protein response and mitophagy [6].

In conclusion, Sesn2 is essential for multiple biological functions, including anti-oxidative stress, regulation of mitochondrial function, and cell growth. Through KO/CKO mouse models, its roles in various disease conditions such as sepsis, anthracycline-related cardiotoxicity, DMD, sepsis-induced ferroptosis, and denervated muscle atrophy have been revealed. These findings contribute to understanding the underlying mechanisms of these diseases and may provide potential therapeutic targets.

References:

1. Wang B, Jie, Wang, Shudong, Xiao, Mengjie, Tang, Yufeng, Gu, Junlian. 2020. Regulatory mechanisms of Sesn2 and its role in multi-organ diseases. In Pharmacological research, 164, 105331. doi:10.1016/j.phrs.2020.105331. https://pubmed.ncbi.nlm.nih.gov/33285232/

2. Gao, Ting, Wang, Jie, Xiao, Mengjie, Li, Jiahao, Gu, Junlian. 2023. SESN2-Mediated AKT/GSK-3β/NRF2 Activation to Ameliorate Adriamycin Cardiotoxicity in High-Fat Diet-Induced Obese Mice. In Antioxidants & redox signaling, 40, 598-615. doi:10.1089/ars.2022.0156. https://pubmed.ncbi.nlm.nih.gov/37265150/

3. Kim, Min-Ji, Bae, Soo Han, Ryu, Jae-Chan, Ryu, Ji-Hwan, Yoon, Joo-Heon. 2016. SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages. In Autophagy, 12, 1272-91. doi:10.1080/15548627.2016.1183081. https://pubmed.ncbi.nlm.nih.gov/27337507/

4. Song, Zubiao, Lin, Qing, Liang, Jiahui, Zhang, Weixi. 2024. Inhibition of Sesn2 has negative regulatory effects on the myogenic differentiation of C2C12 myoblasts. In Molecular biomedicine, 5, 31. doi:10.1186/s43556-024-00193-z. https://pubmed.ncbi.nlm.nih.gov/39117956/

5. Li, Jing-Yan, Ren, Chao, Wang, Li-Xue, Tian, Ying-Ping, Yao, Yong-Ming. 2021. Sestrin2 protects dendrite cells against ferroptosis induced by sepsis. In Cell death & disease, 12, 834. doi:10.1038/s41419-021-04122-8. https://pubmed.ncbi.nlm.nih.gov/34482365/

6. Yang, Xiaofan, Xue, Pingping, Yuan, Meng, Machens, Hans-Günther, Chen, Zhenbing. 2021. SESN2 protects against denervated muscle atrophy through unfolded protein response and mitophagy. In Cell death & disease, 12, 805. doi:10.1038/s41419-021-04094-9. https://pubmed.ncbi.nlm.nih.gov/34429398/