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

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.