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

  • Authors:
    • Yadi Ju
    • Xiaodan Chong
    • Weichen Ning
    • Yan Shi
    • Yangyang Li
    • Yihai Shi
  • View Affiliations / Copyright

    Affiliations: School of Gongli Hospital Medical Technology, University of Shanghai for Science and Technology, Shanghai 200093, P.R. China, Clinical Oncology Institute, Center for Translational Medicine, Naval Medical University, Shanghai 200433, P.R. China, School of Gongli Hospital Medical Technology, University of Shanghai for Science and Technology, Shanghai 200093, P.R. China, Clinical Oncology Institute, Center for Translational Medicine, Naval Medical University, Shanghai 200433, P.R. China, Department of Gastroenterology, Gongli Hospital, Shanghai 200135, P.R. China
    Copyright: © Ju et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 206
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    Published online on: May 22, 2026
       https://doi.org/10.3892/mmr.2026.13916
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Abstract

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.
View Figures

Figure 1

Main families of Ub ligases and DUBs
and their core features. E3 Ub ligases (key subtypes) mainly
include HECT (with C-terminal HECT domain), RING (with N-terminal
zinc-binding RING domain), U-box (with C-terminal U-box domain) and
RBR (with RING1/IBR/RING2 domains). DUBs (main families) mainly
include USP, UCHL and OTU families, and the domain composition of
these families (such as catalytic domains and accessory domains of
USP) is described. Ub, ubiquitin; E1, ubiquitin-activating enzyme;
E2, ubiquitin-conjugating enzyme; E3, ubiquitin ligase; RING,
really interesting new gene; HECT, homologous to E6-AP C-terminus;
RBR, RING-between-RING; DUBs, deubiquitinating enzymes; USP,
ubiquitin-specific protease; UCH, ubiquitin C-terminal hydrolase;
OTU, ovarian tumor protease; UCHL3, ubiquitin C-terminal hydrolase
L3; BAP1, BRCA1-associated protein 1; A20, TNF-α-induced protein 3;
OTUB1, OTU domain-containing ubiquitin aldehyde-binding protein 1;
OTUD5, OTU deubiquitinase 5.

Figure 2

Hepatic ubiquitin system-mediated
homeostatic regulatory networks under physiological conditions. Key
components (such as A20, CYLD, Fbw7, PINK1-PARKIN and MARCH5)
acting across pathways: i) Fine-tuning immune responses downstream
of TLR4, TCR and TNFR signaling; ii) governing metabolic pathways
via regulators such as Fbw7; and iii) executing protein quality
control through the PINK1-PARKIN axis and MARCH5. The coordinated,
context-dependent actions of these components underpin hepatic
functional homeostasis. TLR4, Toll-like receptor 4; MyD88, myeloid
differentiation primary response 88; IRAK1/4, interleukin-1
receptor-associated kinase 1/4; TRAF6, TNF receptor-associated
factor 6; A20, TNF-α-induced protein 3; TAB2/3, TAK1-binding
protein 2/3; TAK1, TGF-β-activated kinase 1; CYLD, cylindromatosis;
NEMO, NF-κB essential modulator; IKKα/β, IκB kinase α/β; NF-κB,
nuclear factor κB; TCR, T-cell receptor; Cbl-b, casitas B-lineage
lymphoma-b; Itch, itchy E3 ubiquitin ligase; PKCθ, protein kinase C
θ; PLCγ1, phospholipase C γ1; Fbw7, F-box/WD repeat-containing
protein 7; SREBP-1c, sterol regulatory element-binding protein 1c;
PINK1, PTEN-induced kinase 1; PARKIN, Parkin RBR E3 ubiquitin
ligase; MARCH5, membrane-associated RING-CH 5; NLRP3, NOD-like
receptor family pyrin domain-containing 3; Ub, ubiquitin; K48,
lysine 48; K63, lysine 63.

Figure 3

Metabolic stress-driven dysregulation
of hepatic ubiquitin system nodes and pathogenic initiation,
including impaired PINK1-PARKIN mitochondrial quality control
(linked to mitochondrial ROS/oxmDNA release), BRCC3
(deubiquitinase) activation that relieves NLRP3 inflammasome
inhibition and suppressed protective E3 ligase MARCH5. These
altered ubiquitin-modifying enzyme nodes are repurposed from
homeostatic guardians to drivers of pathogenic events (such as
NLRP3-dependent IL-18/1β secretion) initiating hepatic pathology.
PINK1, PTEN-induced kinase 1; PARKIN, Parkin RBR E3 ubiquitin
ligase; TRIM31, tripartite motif-containing 31; BRCC3,
BRCA1-BRCA2-containing complex subunit 3; NLRP3, NOD-like receptor
family pyrin domain-containing 3; IL-1β, interleukin-1β; cGAMP,
cyclic GMP-AMP; STING, stimulator of interferon genes.

Figure 4

Schematic of ubiquitin system
reprogramming in hepatocarcinogenesis and PROTAC therapeutic
potential. During hepatocarcinogenesis, ubiquitin system rewiring
drives tumorigenesis via four core alterations: i) CSN5-stabilized
PD-L1 engages PD-1 on T-cells for immune evasion; ii) MDM2
(p53-induced) + USP7 promote p53 ubiquitination and proteasomal
degradation; iii) impaired β-TrCP + enhanced USP22 block c-Myc
ubiquitination, causing its accumulation; and iv) TRIM29 mediates
STING ubiquitination, inhibiting the cGAS-STING pathway. These
changes foster a tumor-promoting microenvironment. PROTAC may
selectively degrade key nodes, although delivery/resistance
challenges remain. PROTACs (proteolysis-targeting chimeras) offer a
potential strategy to selectively degrade key oncogenic nodes
within this reprogrammed network. PD-1, programmed death 1; PD-L1,
programmed death-ligand 1; FBXO38, F-box only protein 38; SPOP,
Speckle-type POZ protein; CSN5, COP9 signalosome subunit 5; cGAS,
cyclic GMP-AMP synthase; STING, stimulator of interferon genes;
TBK1, TANK-binding kinase 1; IRF3, interferon regulatory factor 3;
MDM2, mouse double minute 2 homolog; USP7, ubiquitin-specific
protease 7; p53, tumor protein p53; β-TrCP, β-transducin
repeat-containing protein; c-Myc, cellular myelocytomatosis
oncogene; RNF5, ring finger protein 5; TRIM29, tripartite
motif-containing 29; PROTAC, proteolysis-targeting chimera; Ub,
ubiquitin.
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Copy and paste a formatted citation
Spandidos Publications style
Ju Y, Chong X, Ning W, Shi Y, Li Y and Shi Y: Reprogramming of the hepatic ubiquitin‑immune axis: A unifying mechanism in liver disease progression (Review). Mol Med Rep 34: 206, 2026.
APA
Ju, Y., Chong, X., Ning, W., Shi, Y., Li, Y., & Shi, Y. (2026). Reprogramming of the hepatic ubiquitin‑immune axis: A unifying mechanism in liver disease progression (Review). Molecular Medicine Reports, 34, 206. https://doi.org/10.3892/mmr.2026.13916
MLA
Ju, Y., Chong, X., Ning, W., Shi, Y., Li, Y., Shi, Y."Reprogramming of the hepatic ubiquitin‑immune axis: A unifying mechanism in liver disease progression (Review)". Molecular Medicine Reports 34.1 (2026): 206.
Chicago
Ju, Y., Chong, X., Ning, W., Shi, Y., Li, Y., Shi, Y."Reprogramming of the hepatic ubiquitin‑immune axis: A unifying mechanism in liver disease progression (Review)". Molecular Medicine Reports 34, no. 1 (2026): 206. https://doi.org/10.3892/mmr.2026.13916
Copy and paste a formatted citation
x
Spandidos Publications style
Ju Y, Chong X, Ning W, Shi Y, Li Y and Shi Y: Reprogramming of the hepatic ubiquitin‑immune axis: A unifying mechanism in liver disease progression (Review). Mol Med Rep 34: 206, 2026.
APA
Ju, Y., Chong, X., Ning, W., Shi, Y., Li, Y., & Shi, Y. (2026). Reprogramming of the hepatic ubiquitin‑immune axis: A unifying mechanism in liver disease progression (Review). Molecular Medicine Reports, 34, 206. https://doi.org/10.3892/mmr.2026.13916
MLA
Ju, Y., Chong, X., Ning, W., Shi, Y., Li, Y., Shi, Y."Reprogramming of the hepatic ubiquitin‑immune axis: A unifying mechanism in liver disease progression (Review)". Molecular Medicine Reports 34.1 (2026): 206.
Chicago
Ju, Y., Chong, X., Ning, W., Shi, Y., Li, Y., Shi, Y."Reprogramming of the hepatic ubiquitin‑immune axis: A unifying mechanism in liver disease progression (Review)". Molecular Medicine Reports 34, no. 1 (2026): 206. https://doi.org/10.3892/mmr.2026.13916
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