Protein aggregates as a hallmark of severe alcohol-related liver damage
Alcohol-related liver disease (ALD) remains the leading cause of cirrhosis and liver-related mortality worldwide, and there are few effective treatments. In alcohol-associated hepatitis (AH), hepatocytes often contain Mallory-Denk bodies, which are cytoplasmic membraneless protein aggregates primarily composed of keratin, ubiquitin, and the adapter protein SQSTM1/p62. For decades, MDBs have primarily been seen as histological hallmarks of severe diseases, but it was unclear whether MDBs actively cause injury or represent a cellular coping strategy.
At the same time, stress granules (SGs), dynamic assemblies of RNA-binding proteins and untranslated mRNAs, have emerged as important regulators of cellular stress responses. Both MDB and SG share characteristics of phase-separated protein assemblies, raising the possibility of cooperative regulation during alcohol-induced stress.
Human evidence: p62-positive aggregates dominate the AH liver
In this study, we analyzed liver tissue from AH patients and healthy controls. Immunohistochemistry and biochemical fractionation revealed significant enrichment of p62-positive MDB and SG markers in AH liver, especially in the detergent-insoluble fraction. Electron microscopy confirmed the presence of dense membraneless aggregates in the affected hepatocytes. These observations demonstrate that both MDB and SG accumulate in human AH and are closely associated with p62 aggregation.
Modeling alcohol damage in mice
To elucidate the mechanism, the authors used a chronic overeating (‘Gao-binge’) alcohol model alone or in combination with a DDC diet, which strongly induces MDB. When given alcohol alone, wild-type mice produced only moderate MDB and SG formation, reflecting the limited severity of many rodent ALD models. In contrast, DDC ingestion significantly promoted MDB formation and liver damage, and subsequent alcohol exposure further stressed hepatocytes.
Importantly, genetic deletion of p62 consistently reduced the formation of insoluble MDB and SG components across models. Despite having fewer aggregates, p62-deficient mice often show more severe liver damage, suggesting that aggregate formation itself may be beneficial rather than harmful.
p62: Required for formation, unnecessary for clearance
An important conceptual advance from this study is the separation of MDB formation and clearance. Although p62 is a well-known autophagy receptor, this study shows that loss of p62 does not prevent the eventual resolution of MDB after cessation of noxious stimuli. Instead, p62 appears to be important for assembling large insoluble aggregates but is not essential for their removal by autophagy.
This difference questions the assumption that reducing aggregates will necessarily protect the liver. Instead, p62-mediated sequestration of misfolded and ubiquitinated proteins into MDBs and SGs may alleviate proteotoxic stress by converting more toxic soluble species into inactive inclusion bodies.
Stress granules and adaptive hepatoprotection
The findings also reveal the relationship between MDB and SG. Exposure to alcohol induced moderate SG formation together with MDB, whereas MDB formation by DDC mainly occurred independently of SG. This suggests that different stress situations selectively engage these aggregation pathways. Importantly, both structures are reduced in p62-deficient mice, which also correlates with increased susceptibility to liver injury.
Implications for research and treatment
Together, these data support a model in which p62-dependent protein aggregation represents an adaptive response to chronic alcohol stress. MDB and related assemblies are not purely pathological and may buffer hepatocytes against overwhelming proteotoxicity. Therefore, therapeutic strategies aimed at blocking aggregate formation indiscriminately may be counterproductive.
Instead, future studies may focus on modulating the balance between aggregate formation and clearance or enhancing downstream protective pathways such as NRF2 signaling. This study also highlights the need for sophisticated animal models that better capture the complex stress landscape of human AH.
sauce:
Jilin University First Hospital
Reference magazines:
Hintz, K. others. (2025). Role of SQSTM1/p62 in regulating Mallory-Denk bodies in alcohol-related liver disease. e Gastroenterology. DOI: 10.1136/egastro-2025-100262. https://egastroenterology.bmj.com/content/3/4/e100262
