| Background: G protein-coupled receptors (GPCRs) play diverse roles in physiology and are common drug targets. However, their involvement in liver fibrosis and liver-related events (LREs) in chronic liver disease remains poorly understood. Methods: We investigated GPCRs' role in liver fibrosis and LREs using the NAFLD comprehensive gene expression dataset (GSE49541). We identified lysophosphatidic acid receptor 1 (LPAR1) as associated with advanced liver fibrosis (F3-4) compared to early-stage fibrosis (F0-1) (adj. log FC= 0.281, p=0.016). Combining data from in-house MASLD liver biopsies, serum, and the HCC dataset (by Gyorffy), we explored LPAR1 expression mechanisms and its implications for liver pathology. Results: Analysis of MASLD liver tissue (n=141) revealed a positive correlation between LPAR1 expression and fibrosis stage (r=0.337, p<0.001). Higher LPAR1 expression correlated with increased LRE incidence (n=11, log-rank, P=0.006). Serum autotaxin (ATX) levels, correlated with hepatic LPAR1 expression (r=0.264, p=0.003), were elevated in LRE individuals compared to non-LRE (1.6 vs. 0.9 mg/L, p<0.001). In the HCC dataset (n=364), high LPAR1 expression in tumors correlated with higher mortality (log-rank, P=0.032). Gene analysis associated LPAR1 expression with RhoA/ROCK-YAP/TAZ, suggesting Gα12/13-dependent signaling. Conclusion: The ATX-LPAR1-RhoA signaling axis emerges as a novel pathway in liver fibrosis and LREs. Targeting this pathway may hold therapeutic potential, emphasizing the need for further mechanistic elucidation and therapeutic exploration. |
