GHSR and TLR4 collectively promote hepatic inflammation and aberrant repair in alveolar echinococcosis.

BACKGROUND AND OBJECTIVE: Alveolar echinococcosis (AE) is a fatal zoonotic parasitic disease that causes progressive hepatic injury through chronic inflammation, aberrant proliferative repair, and liver fibrosis. GHSR and TLR4 individually regulate hepatic inflammation and proliferation; however, their synergistic roles in Echinococcus multilocularis (E. multilocularis)-induced AE remain unclear. METHODS: Wild-type (WT), GHSR-knockout (GHSR-/-), and TLR4-knockout (TLR4-/-) murine AE models were established, and comprehensive evaluations of hepatic pathology, cell proliferation, macrophage polarization, inflammatory factors, and hepatic proteomic profiles were performed at 12 weeks post-infection. RESULTS: Knockout of either GHSR or TLR4 alleviated AE-induced hepatic lesions, fibrosis, and liver dysfunction. Mechanistically, their deletion suppressed PI3K/Akt-mediated proliferation and TLR4/MyD88/NF-κB-mediated inflammation, reduced M1/M2 macrophage infiltration, decreased pro-inflammatory cytokines (IL-6, TNF-α, and TGF-β1), and elevated anti-inflammatory IL-10. A positive expression correlation between GHSR and TLR4 was confirmed in AE, Proteomics further verified their coordinated modulation of hepatic inflammation and aberrant repair. CONCLUSIONS: Collectively, upregulated GHSR and TLR4 jointly promote Echinococcus multilocularis-associated hepatic damage via sustaining persistent inflammation and dysregulated proliferative tissue repair. This study demonstrates coordinated pro-pathological involvement of GHSR and TLR4 in AE progression and provides in vivo and proteomic evidence supporting the exploration of targeted interventions against parasitic liver disorders.