A Novel Combination Therapy with Uridine and Praziquantel effectively Alleviates Schistosomiasis-induced Hepatic Fibrosis through Promoting Adipogenic Differentiation
Schistosomiasis-induced hepatic fibrosis, a consequence of egg-induced granulomatous lesions, remains untreated by current drugs. Therefore, the development of novel antifibrosis drugs is of paramount importance. Our previous study indicated that aberrant uridine concentrations play a pivotal role in schistosomiasis-induced hepatic fibrosis. This study aimed to explore the inhibitory role of uridine in schistosomiasis-induced liver fibrosis and the regulatory mechanism of uridine on hepatic stellate cell (HSC) activation. The results indicated that uridine could inhibit schistosomiasis-induced liver fibrosis in vivo and TGF-ß-induced HSC activation in vitro. Molecular docking revealed a strong interaction between uridine and the adenosine receptor A1 (ADORA1) receptor. Subsequent in vitro investigations demonstrated that uridine modulated the cAMP/PKA/CREB pathway, influencing HSC adipogenic differentiation and exerting an antifibrotic effect. In addition, compared with praziquantel (PZQ) alone, combined uridine and PZQ therapy resulted in a reduced fibrotic area and improved hepatic parameters in vivo. Our study reveals the antifibrosis mechanism of the uridine molecule, which may be a promising drug for the treatment of schistosomiasis-induced liver fibrosis. Overall design: RNA-Seq profiling of LX-2 cells, TGF-ß induced LX-2 cells, and Uridine/TGF-ß treated LX-2 cells.