Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol. 2011;6:425–56.

Article  PubMed  Google Scholar 

Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol. 2019;70:151–71.

Article  PubMed  Google Scholar 

GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789–858.

Article  Google Scholar 

Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, Castellanos M, Aller-de la Fuente R, Metwally M, et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. Gastroenterology. 2018;155:443–57.e17.

Article  PubMed  Google Scholar 

Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389–97.e10.

Article  PubMed  Google Scholar 

Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair:immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014;14:181–94.

Article  PubMed  Google Scholar 

Chalasani N, Abdelmalek MF, Garcia-Tsao G, Vuppalanchi R, Alkhouri N, Rinella M, et al. Effects of belapectin, an inhibitor of galectin-3, in patients with nonalcoholic steatohepatitis with cirrhosis and portal hypertension. Gastroenterology. 2020;158:1334–45.e5.

Article  PubMed  Google Scholar 

Harrison SA, Wong VW, Okanoue T, Bzowej N, Vuppalanchi R, Younes Z, et al. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: results from randomized phase III STELLAR trials. J Hepatol. 2020;73:26–39.

Article  PubMed  Google Scholar 

Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019;394:2184–96.

Article  PubMed  Google Scholar 

Eaton JE, Vuppalanchi R, Reddy R, Sathapathy S, Ali B, Kamath PS. Liver injury in patients with cholestatic liver disease treated with obeticholic acid. Hepatology. 2020;71:1511–4.

Article  PubMed  Google Scholar 

Younossi ZM, Stepanova M, Nader F, Loomba R, Anstee QM, Ratziu V, et al. Obeticholic acid impact on quality of life in patients with nonalcoholic steatohepatitis: REGENERATE 18-month interim analysis. Clin Gastroenterol Hepatol. 2022;20:2050–8.e12.

Article  PubMed  Google Scholar 

Chapman RW, Lynch KD. Obeticholic acid-a new therapy in PBC and NASH. Br Med Bull. 2020;133:95–104.

Article  PubMed  Google Scholar 

Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, et al. A Phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390:497–509.

Article  PubMed  Google Scholar 

Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun. 2013;4:2823.

Article  PubMed  Google Scholar 

Hellerbrand C, Stefanovic B, Giordano F, Burchardt ER, Brenner DA. The role of TGFbeta1 in initiating hepatic stellate cell activation in vivo. J Hepatol. 1999;30:77–87.

Article  PubMed  Google Scholar 

Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425:577–84.

Article  PubMed  Google Scholar 

Nakao A, Afrakhte M, Morén A, Nakayama T, Christian JL, Heuchel R, et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature. 1997;389:631–5.

Article  PubMed  Google Scholar 

Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, et al. The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell. 1997;89:1165–73.

Article  PubMed  Google Scholar 

Moustakas A, Souchelnytskyi S, Heldin CH. Smad regulation in TGF-beta signal transduction. J Cell Sci. 2001;114:4359–69.

Article  PubMed  Google Scholar 

Shi W, Sun C, He B, Xiong W, Shi X, Yao D, et al. GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. J Cell Biol. 2004;164:291–300.

Article  PubMed  PubMed Central  Google Scholar 

Dooley S, Hamzavi J, Breitkopf K, Wiercinska E, Said HM, Lorenzen J, et al. Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats. Gastroenterology. 2003;125:178–91.

Article  PubMed  Google Scholar 

Hamzavi J, Ehnert S, Godoy P, Ciuclan L, Weng H, Mertens PR, et al. Disruption of the Smad7 gene enhances CCI4-dependent liver damage and fibrogenesis in mice. J Cell Mol Med. 2008;12:2130–44.

Article  PubMed  PubMed Central  Google Scholar 

Chung AC, Dong Y, Yang W, Zhong X, Li R, Lan HY. Smad7 suppresses renal fibrosis via altering expression of TGF-β/Smad3-regulated microRNAs. Mol Ther. 2013;21:388–98.

Article  PubMed  Google Scholar 

He J, Sun X, Qian KQ, Liu X, Wang Z, Chen Y. Protection of cerulein-induced pancreatic fibrosis by pancreas-specific expression of Smad7. Biochim Biophys Acta. 2009;1792:56–60.

Article  PubMed  Google Scholar 

Nakao A, Fujii M, Matsumura R, Kumano K, Saito Y, Miyazono K, et al. Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. J Clin Invest. 1999;104:5–11.

Article  PubMed  PubMed Central  Google Scholar 

Yang Y, Sun M, Li W, Liu C, Jiang Z, Gu P, et al. Rebalancing TGF-β/Smad7 signaling via Compound kushen injection in hepatic stellate cells protects against liver fibrosis and hepatocarcinogenesis. Clin Transl Med. 2021;11:e410.

Article  PubMed  PubMed Central  Google Scholar 

Liu J, Kong D, Qiu J, Xie Y, Lu Z, Zhou C, et al. Praziquantel ameliorates CCl4 -induced liver fibrosis in mice by inhibiting TGF-β/Smad signalling via up-regulating Smad7 in hepatic stellate cells. Br J Pharmacol. 2019;176:4666–80.

Article  PubMed  PubMed Central  Google Scholar 

Xu X, Guo Y, Luo X, Shen Z, Sun Z, Shen B, et al. Hydronidone ameliorates liver fibrosis by inhibiting activation of hepatic stellate cells via Smad7-mediated degradation of TGFβRI. Liver Int. 2023;43:2523–37.

Article  PubMed  Google Scholar 

Yu LX, Schwabe RF. The gut microbiome and liver cancer: mechanisms and clinical translation. Nat Rev Gastroenterol Hepatol. 2017;14:527–39.

Article  PubMed  PubMed Central  Google Scholar 

Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology. 2014;146:1513–24.

Article  PubMed  Google Scholar 

Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology. 2003;37:1043–55.

Article  PubMed  Google Scholar 

Zhu Q, Zou L, Jagavelu K, Simonetto DA, Huebert RC, Jiang ZD, et al. Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice. J Hepatol. 2012;56:893–9.

Article  PubMed  Google Scholar 

Mazagova M, Wang L, Anfora AT, Wissmueller M, Lesley SA, Miyamoto Y, et al. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J. 2015;29:1043–55.

Article  PubMed  Google Scholar 

De Minicis S, Rychlicki C, Agostinelli L, Saccomanno S, Candelaresi C, Trozzi L, et al. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology. 2014;59:1738–49.

Article  PubMed  Google Scholar 

Loomba R, Seguritan V, Li W, Long T, Klitgord N, Bhatt A, et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab. 2017;25:1054–62.e5.