Reprogramming of the hepatic ubiquitin‑immune axis: A unifying mechanism in liver disease progression (Review).

The progression of liver disease from steatosis to hepatocellular carcinoma has previously been interpreted as a sequential pathological continuum. In the present review, an integrated paradigm wherein this progression arises fundamentally from systematic reprogramming of the ubiquitin code within the hepatic microenvironment was proposed. Under sustained pathological stress, key E3 ligases and deubiquitinases undergo functional remodeling, transitioning from homeostatic guardians to pathogenic drivers of disease. The mechanism by which this reprogramming forms a central axis governing disease progression was systemically illustrated. During initiation, it disrupts inflammasome regulation and mitophagy; throughout progression, it dismantles immune tolerance and activates cell death pathways; and in advanced stages, it stabilizes oncoproteins, degrades tumor suppressors and facilitates immune evasion. Building upon this mechanistic model, novel therapeutic strategies aimed at achieving a functional reset of the dysregulated ubiquitin system via targeted protein degradation were further explored. This approach offers a transformative framework for intercepting the malignant progression of liver disease and presents new prospects for clinical intervention.