TAF and TDF attenuate liver fibrosis through NS5ATP9, TGFβ1/Smad3, and NF-κB/NLRP3 inflammasome signaling pathways
This study aimed to investigate the roles and mechanisms of tenofovir alafenamide fumarate (TAF)/tenofovir disoproxil fumarate (TDF) in treating liver fibrosis.
The effects of TAF/TDF on carbon tetrachloride (CCl4)-induced liver fibrosis in C57BL/6 wild-type or nonstructural protein 5A transactivated protein 9 (NS5ATP9) knockout mice were studied. The differentiation, activation, and proliferation of LX-2 cells after TAF/TDF treatment were tested in vitro. The expression of NS5ATP9 and activities of transforming growth factor-β1 (TGFβ1)/Sekelsky mothers against decapentaplegic homolog 3 (Smad3) and NF-κB/NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome signaling pathways were detected in TAF/TDF-treated mice and LX-2 cells. The genes related to extracellular matrix accumulation were detected in vivo and in vitro after NS5ATP9 silencing or knockout.
TAF/TDF significantly inhibited CCl4-induced liver fibrosis in mice, and regulated the differentiation, activation, and proliferation of hepatic stellate cells (HSCs). Furthermore, TAF/TDF suppressed the activities of TGFβ1/Smad3 and NF-κB/NLRP3 inflammasome signaling pathways in vivo and in vitro. NS5ATP9 inhibited liver fibrosis through TGFβ1/Smad3 and NF-κB signaling pathways. TAF/TDF upregulated the expression of NS5ATP9 in vivo and in vitro. Finally, TAF/TDF could only show marginal therapeutic effects when NS5ATP9 was silenced and knocked out in vivo and in vitro.
TAF/TDF prevented progression and promoted reversion of liver fibrosis through assembling TGFβ1/Smad3 and NF-κB/NLRP3 inflammasome signaling pathways via upregulating the expression of NS5ATP9. TAF/TDF also regulated the differentiation, activation, and proliferation of HSCs. The findings provided strong evidence for the role of TAF/TDF as a new promising therapeutic strategy in liver fibrosis.
KeywordsTAF TDF Liver fibrosis NS5ATP9
JC designed the experiments. JZ performed the experiments and wrote the manuscript. MH and LZ performed most of the experiments involving cells. PL performed molecular, biochemical assays, and participated in the revision of the manuscript. YW, SF, and HL provided NS5ATP9-KO mice. XY and KH analyzed and interpreted the data. XC performed molecular and biochemical assays.
This study was supported by the National Natural Science Foundation of China (No. 81470863 and No. 81670547), the National Key Research and Development Program of China (No. 2017YFC0908100 / 2017YFC0908104), the Beijing Municipal Administration of Hospitals (XMLX201711 to JC), the Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20151701), and the National Science and Technology Major Project (No. 2017ZX10302201-005-004 and No. 2017ZX10202202-005-008). Support was also provided by the Program of Beijing Advanced Innovation Center for Big Data-Based Precision Medicine and the Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.
Compliance with ethical standards
Conflict of interest
Jing Zhao, Ming Han, Li Zhou, Pu Liang, Yun Wang, Shenghu Feng, Hongping Lu, Xiaoxue Yuan, Kai Han, Xiaofan Chen, Shunai Liu, and Jun Cheng declare that they have no competing interests.
Statement of human and animal rights
a) Statement of human rights: this chapter does not contain any studies with human participants performed by any of the authors. b) Statement on welfare of animals: all procedures performed in studies involving animals were in accordance with the ethical standards of Institute Research Ethics Committee of Beijing Ditan Hospital. The entire study was approved by the Institute Research Ethics Committee of Beijing Ditan Hospital.
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