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A tale of dual role: HECT‑type E3 ubiquitin ligase mechanisms in liver diseases (Review)

  • Authors:
    • Tongxi Li
    • Hao Chen
    • Peng Zhao
    • Chuanzheng Yin
    • Zifang Song
  • View Affiliations / Copyright

    Affiliations: Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
    Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 154
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    Published online on: April 7, 2026
       https://doi.org/10.3892/ijmm.2026.5825
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Abstract

HECT‑type E3 ubiquitin ligases play crucial and complex roles in liver diseases such as metabolic dysfunction‑associated steatotic liver disease (MASLD), metabolic dysfunction‑associated steatohepatitis (MASH), liver fibrosis, viral hepatitis and hepatocellular carcinoma (HCC). In MASLD/MASH, these enzymes regulate lipid homeostasis and inflammatory signaling through bidirectional modulation of key metabolic pathways, including PPARα‑SREBP, JAK‑STAT and MAPK cascades. During liver fibrosis, specific HECT members simultaneously promote TGF‑β/Smad signaling by ubiquitinating Smad7 while limiting extracellular matrix deposition through the degradation of TGF‑β receptors. In viral hepatitis, they restrict viral replication via direct ubiquitination and proteasomal degradation of viral proteins yet concurrently facilitate viral release by hijacking the host ESCRT machinery. In HCC, these ligases critically influence tumor progression through opposing mechanisms: Acting as oncogenic drivers by destabilizing tumor suppressors such as PTEN, while functioning as tumor suppressors by degrading oncoproteins including c‑Myc and β‑catenin to attenuate proliferative signaling. Collectively, the ‘dual‑role’ behavior of HECT‑type E3 ligases is governed by disease‑specific contexts, substrate selection, ubiquitin linkage type (K48 vs. K63), and integration of microenvironmental cues. Although this functional duality presents significant translational challenges, understanding these dual regulatory networks provides critical insights into the pathogenesis of liver diseases and reveals potential avenues for targeted interventions.
View Figures

Figure 1

Structural characterization of
HECT-type E3 ubiquitin ligases. The prevalent structure of the
NEDD4 family of HECTs is a C2 structural domain at the N-terminus
with 2-4 tryptophan-within-tryptophan (WW) structural domains in
the middle, whereas the HECT structural domains are at the
C-terminus. The HERC-type subfamily contains at least one RCC1
structural domain at its N-terminus, whereas the HECT structural
domain is at the C-terminus, with the intervening structural
domains The intermediate domains vary. The other HECT-type E3
enzymes all have a HECT structure at the C-terminus, but the
N-terminal and intermediate domains are often disordered and cannot
be categorized.

Figure 2

Role of HECT-type E3 ubiquitin
ligases involved in MASLD/MASH. NEDD4L and ITCH exhibit a classic
dual-role effect in the course of MASLD/MASH. NEDD4L may mediate
steatosis through specific pathways regardless of whether it is up-
or downregulated. Meanwhile, the inherent ITCH upregulation in
MASLD/MASH simultaneously exerts both steatosis-suppressing and
inflammation-promoting effects. ARID2, AT-rich interactive domain
2; TxNIP, thioredoxin interacting protein; LAPTM5,
lysosomal-associated protein transmembrane domain 5; CDC42, cell
division cycle 42 protein; SIRT 6, sirtuin 6; SREBP2, sterol
regulatory element-binding protein 2; LKB1, liver kinase B1; BCAA,
branched-chain amino acid. MASLD, metabolic dysfunction-associated
steatotic liver disease; MASH, metabolic dysfunction-associated
steatohepatitis.

Figure 3

Role of HECT-type E3 ubiquitin
ligases involved in HCC. In HCC, PTEN, as a classic tumor
suppressor gene, can undergo ubiquitination and degradation by
multiple HECT-type E3 ubiquitin ligases. Among these, NEDD4 holds
the greatest translational potential as a HECT-type E3 ubiquitin
ligase target due to its ability to simultaneously activate
multiple signaling pathways and exert oncogenic effects. WWP1,
however, exhibits a classic 'dual role' effect in HCC. It can both
suppress tumor growth and potentially promote tumor invasion and
metastasis. HCC, hepatocellular carcinoma; TGFBR1, TGF-β type I
receptor; LATS1, large tumor suppressor kinase 1; PKM2, pyruvate
kinase M2; ARHGAP24, RhoGAP 24; CPSF7, cleavage and polyadenylation
specificity factor 7; USP13, ubiquitin specific peptidase 13.
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Spandidos Publications style
Li T, Chen H, Zhao P, Yin C and Song Z: A tale of dual role: HECT‑type E3 ubiquitin ligase mechanisms in liver diseases (Review). Int J Mol Med 57: 154, 2026.
APA
Li, T., Chen, H., Zhao, P., Yin, C., & Song, Z. (2026). A tale of dual role: HECT‑type E3 ubiquitin ligase mechanisms in liver diseases (Review). International Journal of Molecular Medicine, 57, 154. https://doi.org/10.3892/ijmm.2026.5825
MLA
Li, T., Chen, H., Zhao, P., Yin, C., Song, Z."A tale of dual role: HECT‑type E3 ubiquitin ligase mechanisms in liver diseases (Review)". International Journal of Molecular Medicine 57.6 (2026): 154.
Chicago
Li, T., Chen, H., Zhao, P., Yin, C., Song, Z."A tale of dual role: HECT‑type E3 ubiquitin ligase mechanisms in liver diseases (Review)". International Journal of Molecular Medicine 57, no. 6 (2026): 154. https://doi.org/10.3892/ijmm.2026.5825
Copy and paste a formatted citation
x
Spandidos Publications style
Li T, Chen H, Zhao P, Yin C and Song Z: A tale of dual role: HECT‑type E3 ubiquitin ligase mechanisms in liver diseases (Review). Int J Mol Med 57: 154, 2026.
APA
Li, T., Chen, H., Zhao, P., Yin, C., & Song, Z. (2026). A tale of dual role: HECT‑type E3 ubiquitin ligase mechanisms in liver diseases (Review). International Journal of Molecular Medicine, 57, 154. https://doi.org/10.3892/ijmm.2026.5825
MLA
Li, T., Chen, H., Zhao, P., Yin, C., Song, Z."A tale of dual role: HECT‑type E3 ubiquitin ligase mechanisms in liver diseases (Review)". International Journal of Molecular Medicine 57.6 (2026): 154.
Chicago
Li, T., Chen, H., Zhao, P., Yin, C., Song, Z."A tale of dual role: HECT‑type E3 ubiquitin ligase mechanisms in liver diseases (Review)". International Journal of Molecular Medicine 57, no. 6 (2026): 154. https://doi.org/10.3892/ijmm.2026.5825
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