| First Author | Li T | Year | 2024 |
| Journal | Cell Death Dis | Volume | 15 |
| Issue | 6 | Pages | 453 |
| PubMed ID | 38926362 | Mgi Jnum | J:354141 |
| Mgi Id | MGI:7661423 | Doi | 10.1038/s41419-024-06798-0 |
| Citation | Li T, et al. (2024) TRIM26 deficiency enhancing liver regeneration through macrophage polarization and beta-catenin pathway activation. Cell Death Dis 15(6):453 |
| abstractText | Liver regeneration is a complex process involving the crosstalk between parenchymal and non-parenchymal cells, especially macrophages. However, the underlying mechanisms remain incompletely understood. Here, we identify the E3 ubiquitin ligase TRIM26 as a crucial regulator of liver regeneration. Following partial hepatectomy or acute liver injury induced by carbon tetrachloride, Trim26 knockout mice exhibit enhanced hepatocyte proliferation compared to wild-type controls, while adeno-associated virus (AAV)-mediated overexpression of Trim26 reverses the promotional effects. Mechanistically, Trim26 deficiency promotes the recruitment of macrophages to the liver and their polarization towards pro-inflammatory M1 phenotype. These M1 macrophages secrete Wnts, including Wnt2, which subsequently stimulate hepatocyte proliferation through the activation of Wnt/beta-catenin signaling. In hepatocytes, Trim26 knockdown reduces the ubiquitination and degradation of beta-catenin, thereby further enhancing Wnt/beta-catenin signaling. Pharmacological inhibition of Wnt/beta-catenin pathway by ICG-001 or depletion of macrophages by clodronate liposomes diminishes the pro-regenerative effects of Trim26 deficiency. Moreover, bone marrow transplantation experiments provide evidence that Trim26 knockout in myeloid cells alone can also promote liver regeneration, highlighting the critical role of macrophage Trim26 in this process. Taken together, our study uncovers TRIM26 as a negative regulator of liver regeneration by modulating macrophage polarization and Wnt/beta-catenin signaling in hepatocytes, providing a potential therapeutic target for promoting liver regeneration in clinical settings. |
