P62/SQSTM1 in liver diseases: the usual suspect with multifarious identities. (18th December 2021)

• Record Type: Journal Article
• Authors: Tan, Chong Teik; Soh, Natalie Jun Hui; Chang, Hao‐Chun; Yu, Victor C.
• Is Part Of: FEBS journal. Volume 290:Number 4(2023)
• Page Start: 892
• Page End: 912
• Publication Date: 2021-12-18
• Subjects: autophagy -- liver cancer -- MOAP‐1 -- non‐alcoholic fatty liver disease -- Nrf2 -- p62 bodies; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.16317
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : p62/Sequestosome‐1 (SQSTM1) is a selective autophagy receptor that recruits and delivers intracellular substrates for bulk clearance through the autophagy lysosomal pathway. Interestingly, p62 also serves as a signaling scaffold to participate in the regulation of multiple physiological processes, including oxidative stress response, metabolism, inflammation, and programmed cell death. Perturbation of p62 activity has been frequently found to be associated with the pathogenesis of many liver diseases. p62 has been identified as a critical component of protein aggregates in the forms of Mallory–Denk bodies (MDBs) or intracellular hyaline bodies (IHBs), which are known to be frequently detected in biopsy samples from alcoholic steatohepatitis (ASH), non‐alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC) patients. Importantly, abundance of these p62 inclusion bodies is increasingly recognized as a biomarker for NASH and HCC. Although the level of p62 bodies seems to predict the progression and prognosis of these liver diseases, understanding of the underlying mechanisms by which p62 regulates and contributes to the development and progression of these diseases remains incomplete. In this review, we will focus on the function and regulation of p62, and its pathophysiological roles in the liver, by critically reviewing the findings from preclinical models that recapitulate the pathogenesis and manifestation of these liver diseases in humans. In addition, we will also explore the suitability of p62 as a predictive biomarker and a potential therapeutic target for the treatment of liver diseases, including NASH and HCC, as well as recent development of small‐molecule compounds for targeting the p62 signaling axis. Abstract : p62/SQSTM1 serves as a selective autophagy receptor and a signaling scaffold to participate in the regulation of multiple physiological processes. Perturbation of p62 activity is associated with liver diseases including fibrosis, non‐alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). In this review, we discuss on the pathophysiological roles of p62 in the liver and explore its suitability as a biomarker and potential therapeutic target for the treatment of NASH and HCC.