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Sestrin2 can protect against atherosclerosis, heart failure, hypertension, myocardial infarction, stroke, spinal cord injury neurodegeneration, nonalcoholic fatty liver disease (NAFLD), liver fibrosis, acute kidney injury (AKI), chronic kidney disease (CKD), and pulmonary inflammation. Oxidative stress and cellular damage signals can alter the expression of Sestrin2 to compensate for organ damage. Different stress signals such as those mediated by P53, Nrf2\/ARE, HIF\u20101<jats:italic>\u03b1<\/jats:italic>, NF\u2010<jats:italic>\u03ba<\/jats:italic>B, JNK\/c\u2010Jun, and TGF\u2010<jats:italic>\u03b2<\/jats:italic>\/Smad signaling pathways can induce Sestrin2 expression. Subsequently, Sestrin2 activates Nrf2 and AMPK. Furthermore, Sestrin2 is a major negative regulator of mTORC1. Sestrin2 indirectly regulates the expression of several genes and reprograms intracellular signaling pathways to attenuate oxidative stress and modulate a large number of cellular events such as protein synthesis, cell energy homeostasis, mitochondrial biogenesis, autophagy, mitophagy, endoplasmic reticulum (ER) stress, apoptosis, fibrogenesis, and lipogenesis. Sestrin2 vigorously enhances M2 macrophage polarization, attenuates inflammation, and prevents cell death. These alterations in molecular and cellular levels improve the clinical presentation of several diseases. This review will shed light on the beneficial effects of Sestrin2 on several diseases with an emphasis on underlying pathophysiological effects.<\/jats:p>","DOI":"10.1155\/2021\/8790369","type":"journal-article","created":{"date-parts":[[2021,11,2]],"date-time":"2021-11-02T17:56:36Z","timestamp":1635875796000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Target Sestrin2 to Rescue the Damaged Organ: Mechanistic Insight into Its Function"],"prefix":"10.1155","volume":"2021","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5951-4864","authenticated-orcid":false,"given":"Moein","family":"Ala","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyed 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