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Role of SQSTM1/p62 in regulating Mallory-Denk body in alcohol-associated liver disease

Kaitlyn Hinz,Hui Qian,Brandon J. Peiffer,Zhaoli Sun,Hong-Min Ni,Wen-Xing Ding

Published 2025 in eGastroenterology

ABSTRACT

Abstract Background Alcohol-associated liver disease (ALD) is a global health problem without an effective treatment. Mallory-Denk body (MDB) is a protein aggregate commonly found in alcohol-associated hepatitis (AH). MDB primarily contains ubiquitinated proteins, cytokeratin 8 and sequestosome 1 (SQSTM1)/p62. Stress granule (SG) is a cytosolic, membrane-less aggregate composed of various RNA-binding proteins and untranslated mRNA. However, the role and mechanisms of MDB and SG induced by alcohol and their implications in the pathogenesis of ALD remain largely unknown. Methods SQSTM1/p62 whole body knockout and matched wild-type mice were subjected to the Gao-binge alcohol model or fed a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet alongside Gao-binge alcohol model. ALD mouse liver tissues and human AH liver tissues underwent immunohistochemistry (IHC) staining and western blot analysis for SG and MDB markers. Results We found that the livers of patients with AH had higher levels of SQSTM1/p62 (MDB marker) and Ras-GTPase-activating protein-binding protein 1 (an SG marker) using IHC staining, and these increased protein levels were enriched in detergent-insoluble fractions compared with healthy individuals. We further discovered that Gao-binge alcohol feeding increased insoluble SG markers, such as phosphorylated eukaryotic initiation factor 2 in mouse livers. Mice fed a DDC diet with Gao-binge alcohol had greater hepatic MDB formation and liver injury than those fed either diet alone. Loss of SQSTM1/p62 led to reduced protein aggregation involved in SGs and MDBs but increased liver injury in DDC plus Gao-binge alcohol-fed mice, indicating that SQSTM1/p62 is required for MDB formation and protects against alcohol-induced liver injury. Conclusion Chronic plus binge alcohol exposure increases hepatic MDBs and moderate levels of SGs. p62/SQSTM1 is critical for the formation but is not essential for the clearance of MDBs, a process that may act as an adaptive protective mechanism against ALD.

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