Protein aggregates as hallmarks of severe alcohol-related liver injury
Alcohol-associated liver disease (ALD) remains a leading cause of cirrhosis and liver-related mortality worldwide, with few effective therapies. In alcohol-associated hepatitis (AH), hepatocytes frequently contain Mallory-Denk bodies, which are cytoplasmic, membrane-less protein aggregates composed mainly of keratins, ubiquitin and the adaptor protein SQSTM1/p62. For decades, MDBs have been viewed largely as histological hallmarks of severe disease, but whether they actively drive injury or represent a cellular coping strategy has been unclear.
In parallel, stress granules (SGs), which are dynamic assemblies of RNA-binding proteins and untranslated mRNA, have emerged as key regulators of cellular stress responses. Both MDBs and SGs share features of phase-separated protein assemblies, raising the possibility of coordinated regulation during alcohol-induced stress.
Human evidence: p62-positive aggregates dominate AH livers
This study analyzed liver tissue from patients with AH and healthy controls. Immunohistochemistry and biochemical fractionation revealed a striking enrichment of p62-positive MDBs and SG markers in AH livers, particularly within detergent-insoluble fractions. Electron microscopy confirmed the presence of dense, membrane-less aggregates in diseased hepatocytes. These observations establish that both MDBs and SGs accumulate in human AH and are closely associated with p62 aggregation.
Modelling alcohol injury in mice
To dissect mechanism, the authors used a chronic-plus-binge ("Gao-binge") alcohol model, alone or combined with a DDC diet that robustly induces MDBs. Alcohol feeding alone produced only modest MDB and SG formation in wild-type mice, mirroring the limited severity of many rodent ALD models. In contrast, DDC feeding markedly enhanced MDB formation and liver injury, and subsequent alcohol exposure further stressed hepatocytes.
Crucially, genetic deletion of p62 consistently reduced the formation of insoluble MDB and SG components across models. Despite fewer aggregates, p62-deficient mice often exhibited worse liver injury, suggesting that aggregate formation itself may not be harmful and may even be beneficial.
p62: required for formation, dispensable for clearance
A key conceptual advance from this work is the separation of MDB formation from clearance. Although p62 is a well-known autophagy receptor, the study shows that loss of p62 does not prevent eventual resolution of MDBs after withdrawal of injurious stimuli. Instead, p62 appears critical for assembling large, insoluble aggregates but is not essential for their autophagic removal.
This distinction challenges the assumption that reducing aggregates will necessarily protect the liver. Instead, p62-mediated sequestration of misfolded and ubiquitinated proteins into MDBs and SGs may reduce proteotoxic stress by converting more toxic soluble species into inert inclusions.
Stress granules and adaptive hepatoprotection
The findings also clarify the relationship between MDBs and SGs. Alcohol exposure induced moderate SG formation alongside MDBs, but DDC-driven MDB formation occurred largely independently of SGs. This suggests that different stress contexts selectively engage these aggregation pathways. Importantly, both structures were diminished in p62-deficient mice, again correlating with increased susceptibility to liver injury.
Implications for research and therapy
Together, the data support a model in which p62-dependent protein aggregation represents an adaptive response to chronic alcohol stress. Rather than being purely pathological, MDBs and related assemblies may buffer hepatocytes against overwhelming proteotoxicity. Therapeutic strategies aimed at indiscriminately blocking aggregate formation could therefore be counterproductive.
Instead, future work may focus on modulating the balance between aggregate formation and clearance, or enhancing downstream protective pathways such as NRF2 signaling. The study also underscores the need for refined animal models that better capture the complex stress landscape of human AH.
See the article:
Hinz K, Qian H, Peiffer B, et al. Role of SQSTM1/ p62 in regulating Mallory-Denk body in alcohol-associated liver disease. eGastroenterology 2025;3:e100262. doi:10.1136/ egastro-2025-100262
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