Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-06, Vol.112 (23), p.7243-7248
• Main Authors: Su, Tung-Hung, Shiau, Chung-Wai, Jao, Ping, Liu, Chen-Hua, Liu, Chun-Jen, Tai, Wei-Tien, Jeng, Yung-Ming, Yang, Hung-Chih, Tseng, Tai-Chung, Huang, Hsiang-Po, Cheng, Huei-Ru, Chen, Pei-Jer, Chen, Kuen-Feng, Kao, Jia-Horng, Chen, Ding-Shinn
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biological Sciences; Cell Line; Cells; Hepatic Stellate Cells - drug effects; Hepatitis; Humans; Liver Cirrhosis - prevention & control; Liver diseases; Male; Mice; Mice, Inbred BALB C; Niacinamide - analogs & derivatives; Niacinamide - chemistry; Niacinamide - pharmacology; Phenylurea Compounds - chemistry; Phenylurea Compounds - pharmacology; Rats; Rodents; Signal transduction; Sorafenib; STAT3 Transcription Factor - antagonists & inhibitors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1507499112

Signal transducer and activator of transcription 3 (STAT3) had been involved in liver fibrogenesis. We aimed to explore the antifibrotic activities of sorafenib and its derivative SC-1 (devoid of Raf kinase inhibition activity) both in vivo and in vitro with special focus on the STAT3 pathway in hepatic stellate cells (HSCs). The clinical role of STAT3 in chronic hepatitis B (CHB) was also investigated. Experimental fibrosis mouse models were established by thioacetamide injection and bile duct ligation in Balb/C mice and treated with sorafenib and SC-1. Rat and human HSCs were used for mechanistic investigations. Forty CHB patients were enrolled to quantify the hepatic phospho-STAT3 (p-STAT3) levels and correlated with liver fibrosis. Both sorafenib and SC-1 ameliorated liver fibrosis in vivo and promoted HSC apoptosis in vitro. p-STAT3 and downstream signals were down-regulated after sorafenib and SC-1 treatment in HSC. STAT3 overexpression in HSC enhanced cell proliferation and undermined the apoptotic effects of sorafenib and SC-1, whereas STAT3-specific inhibition promoted HSC apoptosis. Sorafenib and SC-1 activated Src-homology protein tyrosine phosphatase-1 (SHP-1) and STAT3 inhibition followed. Of particular interest, in CHB patients with advanced liver fibrosis, p-STAT3 in HSC was significantly overexpressed and positively correlated with the severity of liver fibrosis and plasma IL-6 levels. In conclusion, sorafenib and SC-1 ameliorate liver fibrosis through STAT3 inhibition in HSC and STAT3 may potentially serve as a promising fibrotic biomarker and target in liver fibrosis. SHP-1 phosphatase-directed STAT3 inhibition may represent a previously unidentified strategy for antifibrotic drug discovery. Significance The role of signal transducer and activator of transcription 3 (STAT3) pathway in hepatic stellate cells (HSCs) remains unclear. Using sorafenib and its derivative SC-1, we demonstrated the significant role of STAT3 pathway in liver fibrogenesis. We further found that STAT3 pathway of HSCs overexpressed in chronic hepatitis B patients with advanced fibrosis, therefore STAT3 may serve as a promising fibrotic biomarker and target. Furthermore, SHP-1 phosphatase-direct STAT3 inhibition may represent a previously unidentified strategy for antifibrotic drug discovery.