Sestrin2: multifaceted functions, molecular basis, and its implications in liver diseases

Area of Science:

• Cellular Biology
• Molecular Biology
• Hepatology

Background:

• Sestrin2 (SESN2) is a stress-responsive protein induced by various stimuli like hypoxia, DNA damage, oxidative stress, ER stress, and inflammation.
• SESN2 expression is regulated by transcription factors including HIF-1, p53, Nrf2, ATF4, and ATF6.
• SESN2 activation leads to AMPK activation and mTORC1 inhibition, maintaining cellular homeostasis by managing redox, autophagy, ER stress, apoptosis, and inflammation.

Purpose of the Study:

• To review the biological functions of SESN2 under various cellular stresses.
• To emphasize the pathophysiological significance of SESN2 in liver diseases, including NAFLD, hepatic fibrosis, and HCC.
• To provide a comprehensive understanding of SESN2 as a potential therapeutic target for liver diseases.

Main Methods:

• Literature review of studies on Sestrin2 (SESN2) function.
• Analysis of SESN2's role in cellular stress responses.
• Examination of SESN2's involvement in the pathogenesis and progression of liver diseases.

Main Results:

• SESN2 plays a role in maintaining cellular homeostasis by scavenging reactive oxygen species and regulating key cellular processes.
• In NAFLD, SESN2 delays disease progression by balancing glycolipid metabolism, autophagy, oxidative damage, and ER stress.
• SESN2 inhibits hepatic stellate cell activation and inflammation in hepatic fibrosis, but its role in HCC is controversial due to conflicting effects on autophagy and apoptosis.

Conclusions:

• SESN2 is a critical mediator of cellular stress responses.
• SESN2 exhibits protective roles in NAFLD and hepatic fibrosis.
• SESN2 presents a potential therapeutic target for liver diseases, although its role in HCC requires further investigation.