TRIM26 deficiency promotes liver fibrosis progression by mediating macrophage polarization via the EZH2-STAT1 axis

Liver fibrosis, a wound-healing response to chronic injury, can progress to cirrhosis and hepatocellular carcinoma. We investigated Tripartite motif-containing protein 26 (TRIM26) in liver fibrosis and its mechanisms.

TRIM26 knockout (Trim26⁻^/⁻) mice were generated to study Trim26's role in liver fibrosis. Histological analyses, qPCR, and western blotting were conducted to examine fibrosis markers and macrophage activation. In vitro studies examined macrophage polarization and hepatic stellate cells (HSCs) activation. Co-immunoprecipitation and ubiquitination assays were performed to explore the interaction between TRIM26 and enhancer of zeste homolog 2 (EZH2).

TRIM26 expression was significantly downregulated in human cirrhotic tissues and fibrotic mouse livers. In Trim26^⁻/⁻ mice, CCl₄- and BDL-induced fibrosis models exhibited exacerbated collagen deposition, elevated α-smooth muscle actin (α-SMA), and type I collagen (Collagen I) expression, whereas AAV-mediated Trim26 restoration markedly ameliorated these pathological features. Transcriptomic and cellular analyses indicated that Trim26 deficiency increased the pro-inflammatory cytokines, activated NF-κB and STAT1 signaling pathways, enhanced M1 macrophage polarization, and increased inflammatory cell infiltration. In vitro experiments confirmed that conditioned medium from Trim26-deficient macrophages significantly promoted α-SMA and collagen expression in HSCs. Mechanistically, TRIM26 interacts with EZH2, inhibiting TRAF6-mediated K48-linked ubiquitination and degradation to maintain EZH2 stability. EZH2, in turn, suppresses STAT1 transcriptional activity by catalyzing H3K27me3 modification on the STAT1 gene chromatin. EZH2 degradation leads to STAT1 upregulation, exacerbating M1 macrophage polarization.

Trim26 attenuates liver fibrosis by stabilizing EZH2 and regulating macrophage polarization, which reduces HSC activation.