Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18, 1028–1040 (2012).
Rockey, D. C., Bell, P. D. & Hill, J. A. Fibrosis—a common pathway to organ injury and failure. N. Engl. J. Med. 373, 95–96 (2015).
Bataller, R. & Brenner, D. A. Liver fibrosis. J. Clin. Invest. 115, 209–218 (2005).
Friedman, S. L. Liver fibrosis—from bench to bedside. J. Hepatol. 38, 38–53 (2003).
Cox, T. R. & Erler, J. T. Molecular pathways: connecting fibrosis and solid tumor metastasis. Clin. Cancer Res. 20, 3637–3643 (2014).
Cernaro, V. et al. Fibrosis, regeneration and cancer: what is the link? Nephrol. Dial. Transplant. 27, 21–27 (2012).
Rybinski, B., Franco-Barraza, J. & Cukierman, E. The wound healing, chronic fibrosis and cancer progression triad. Physiol. Genomics 46, 223–244 (2014).
Klingler, W., Jurkat-Rott, K., Lehmann-Horn, F. & Schleip, R. The role of fibrosis in Duchenne muscular dystrophy. Acta Myol. 31, 184–195 (2012) http://www.ncbi.nlm.nih.gov/pubmed/23620650.
Torres, V. E. & Leof, E. B. Fibrosis, regeneration, and aging: playing chess with evolution. J. Am. Soc. Nephrol. 22, 1393–1396 (2011).
Hecker, L. et al. Reversal of persistent fibrosis in aging by targeting Nox4–Nrf2 redox imbalance. Sci. Transl. Med. 6, 231ra47 (2014).
Mehal, W. Z., Iredale, J. & Friedman, S. L. Scraping fibrosis: expressway to the core of fibrosis. Nat. Med. 17, 552–553 (2011).
Wynn, T. Cellular and molecular mechanisms of fibrosis. J. Pathol. 214, 199–210 (2008).
Koyama, Y. & Brenner, D. A. Liver inflammation and fibrosis. J. Clin. Invest. 127, 55–64 (2017).
Hayden, M. S. & Ghosh, S. NF-κB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev. 26, 203–234 (2012).
Oeckinghaus, A. & Ghosh, S. The NF-κB family of transcription factors and its regulation. Cold Spring Harb. Perspect. Biol. 1, a000034 (2009).
Lawrence, T. The nuclear factor NF-κB pathway in inflammation. Cold Spring Harb. Perspect. Biol. 1, a001651 (2009).
Tak, P. P. & Firestein, G. S. NF-κB: a key role in inflammatory diseases. J. Clin. Invest. 107, 7–11 (2001).
Zhang, Q., Lenardo, M. J. & Baltimore, D. 30 years of NF-κB: a blossoming of relevance to human pathobiology. Cell 168, 37–57 (2017).
Luedde, T. & Schwabe, R. F. NF-κB in the liver—linking injury, fibrosis and hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 8, 108–118 (2011).
Perkins, N. D. & Gilmore, T. D. Good cop, bad cop: the different faces of NF-κB. Cell Death Differ. 13, 759–772 (2006).
Piva, R., Belardo, G. & Santoro, M. G. NF-κB: a stress-regulated switch for cell survival. Antioxid. Redox Signal. 8, 478–486 (2006).
Wong, D. et al. Extensive characterization of NF-κB binding uncovers non-canonical motifs and advances the interpretation of genetic functional traits. Genome Biol. 12, R70 (2011).
Geisler, F., Algül, H., Paxian, S. & Schmid, R. M. Genetic inactivation of RelA/p65 sensitizes adult mouse hepatocytes to TNF-induced apoptosis in vivo and in vitro. Gastroenterology 132, 2489–2503 (2007).
Rosenfeld, M. E., Prichard, L., Shiojiri, N. & Fausto, N. Prevention of hepatic apoptosis and embryonic lethality in RelA/TNFR-1 double knockout mice. Am. J. Pathol. 156, 997–1007 (2000).
Beg, A. A., Sha, W. C., Bronson, R. T., Ghosh, S. & Baltimore, D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB. Nature 376, 167–170 (1995).
Lenardo, M. J. & Baltimore, D. NF-κB: a pleiotropic mediator of inducible and tissue-specific gene control. Cell 58, 227–229 (1989).
Fullard, N., Wilson, C. L. & Oakley, F. Roles of c-Rel signalling in inflammation and disease. Int. J. Biochem. Cell Biol. 44, 851–860 (2012).
Neo, W. H., Lim, J. F., Grumont, R., Gerondakis, S. & Su, I. c-Rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells. J. Biol. Chem. 289, 31693–31707 (2014).
Zeybel, M. et al. A proof-of-concept for epigenetic therapy of tissue fibrosis: inhibition of liver fibrosis progression by 3-deazaneplanocin A. Mol. Ther. 25, 218–231 (2017).
Fullard, N. et al. The c-Rel subunit of NF-κB regulates epidermal homeostasis and promotes skin fibrosis in mice. Am. J. Pathol. 182, 2109–2120 (2013).
Gaspar-Pereira, S. et al. The NF-κB Subunit c-Rel stimulates cardiac hypertrophy and fibrosis. Am. J. Pathol. 180, 929–939 (2012).
Luli, S. et al. A new fluorescence-based optical imaging method to non-invasively monitor hepatic myofibroblasts in vivo. J. Hepatol. 65, 75–83 (2016).
Hunter, J. E., Leslie, J. & Perkins, N. D. C-Rel and its many roles in cancer: an old story with new twists. Br. J. Cancer. 114, 1–6 (2016).
Schwabe, R. F., Tabas, I. & Pajvani, U. B. Mechanisms of fibrosis development in nonalcoholic steatohepatitis. Gastroenterology 158, 1913–1928 (2020).
Swamy, M., Jamora, C., Havran, W. & Hayday, A. Epithelial decision makers: in search of the ‘epimmunome’. Nat. Immunol. 11, 656–665 (2010).
Duffield, J. S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005).
Seki, E. et al. CCR2 promotes hepatic fibrosis in mice. Hepatology 50, 185–197 (2009).
Wynn, T. A. & Vannella, K. M. Macrophages in tissue repair, regeneration and fibrosis. Immunity 44, 450–462 (2016).
Garcia-Lazaro, J. F. et al. Hepatic over-expression of TGF-β1 promotes LPS-induced inflammatory cytokine secretion by liver cells and endotoxemic shock. Immunol. Lett. 101, 217–222 (2005).
Yang, L. et al. Transforming growth factor-β signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1. Gastroenterology 144, 1042–1054 (2013).
Bird, T. G. et al. TGF-β inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci. Transl. Med. 10, eaan1230 (2018).
Niu L., et al. Involvement of TGF-β1/Smad3 signaling in carbon tetrachloride-induced acute liver injury in mice. PLoS ONE 11, e0156090 (2016).
Travis, M. A. & Sheppard, D. TGF-β activation and function in immunity. Annu Rev. Immunol. 32, 51–82 (2014).
Grgurevic, L. et al. Systemic inhibition of BMP1-3 decreases progression of CCl4-induced liver fibrosis in rats. Growth Factors 35, 201–215 (2017).
Lipson, K. E., Wong, C., Teng, Y. & Spong, S. CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis. Fibrogenesis Tissue Repair 5, S24 (2012).
Fox, C. et al. Inhibition of lysosomal protease cathepsin D reduces renal fibrosis in murine chronic kidney disease. Sci Rep. 6, 20101 (2016).
Moles, A., Tarrats, N., Fernández-Checa, J. C. & Marí, M. Cathepsins B and D drive hepatic stellate cell proliferation and promote their fibrogenic potential. Hepatology 49, 1297–1307 (2009).
Ghosh, A. K. & Vaughan, D. E. PAI-1 in tissue fibrosis. J. Cell. Physiol. 227, 493–507 (2012).
Kodama, T. et al. Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice. J. Clin. Invest. 121, 3343–3356 (2011).
Mathieu, J. & Ruohola-Baker, H. Metabolic remodeling during the loss and acquisition of pluripotency. Development 144, 541–551 (2017).
Sciacovelli, M. & Frezza, C. Metabolic reprogramming and epithelial-to-mesenchymal transition in cancer. FEBS J. 284, 3132–3144 (2017).
Nieto, M. A., Huang, R. Y.-J., Jackson, R. A. & Thiery, J. P. EMT: 2016. Cell 166, 21–45 (2016).
Kelly, B. & O’Neill, L. A. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 25, 771–784 (2015).
Taura, K. et al. Hepatocytes do not undergo epithelial–mesenchymal transition in liver fibrosis in mice. Hepatology 51, 1027–1036 (2010).
Humphreys, B. D. et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am. J. Pathol. 176, 85–97 (2010).
Grande, M. T. et al. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat. Med. 21, 989–997 (2015).
Rowe, R. G. et al. Hepatocyte-derived Snail1 propagates liver fibrosis progression. Mol. Cell. Biol. 31, 2392–2403 (2011).
Hee Kim, N. et al. Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress. Nat. Commun. 8, 14374 (2017).
Mills, E. L. & O’Neill, L. A. Reprogramming mitochondrial metabolism in macrophages as an anti-inflammatory signal. Eur. J. Immunol. 46, 13–21 (2016).
Gieling, R. G. et al. The c-Rel subunit of NF-κB regulates murine liver inflammation, wound healing and hepatocyte proliferation. Hepatology 51, 922–931 (2010).
Shono, Y. et al. A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity. Cancer Discov. 4, 578–591 (2014).
Paish, H. L. et al. A bioreactor technology for modelling fibrosis in human and rodent precision-cut liver slices. Hepatology 70, 1377–1391 (2019).
Nielsen, M. J. et al. Plasma Pro-C3 (N-terminal type III collagen propeptide) predicts fibrosis progression in patients with chronic hepatitis C. Liver Int. 35, 429–437 (2015).
Krawczyk, C. M. et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115, 4742–4749 (2010).
Lees, J. G., Gardner, D. K. & Harvey, A. J. Mitochondrial and glycolytic remodeling during nascent neural differentiation of human pluripotent stem cells. Development 145, dev168997 (2018).
Peng, M. et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481–484 (2016).
Wei, Q. et al. Glycolysis inhibitors suppress renal interstitial fibrosis via divergent effects on fibroblasts and tubular cells. Am. J. Physiol. Renal Physiol. 316, F1162–F1172 (2018).
Ding, H. et al. Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis. Am. J. Physiol. Renal Physiol. 313, F561–F575 (2017).
Xie, N. et al. Glycolytic reprogramming in myofibroblast differentiation and lung fibrosis. Am. J. Respir. Crit. Care Med. 92, 1462–1474 (2015).
MacParland, S. A. et al. Single-cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat. Commun. 9, 4383 (2018).
Chang, N. et al. Single-cell transcriptomes reveal characteristic features of mouse hepatocytes with liver cholestatic injury. Cells. 8, 1069 (2019).
Huang, G. & Brigstock, D. R. Regulation of hepatic stellate cells by connective tissue growth factor. Front. Biosci. 17, 2495–2507 (2012).
Paradis, V. et al. Effects and regulation of connective tissue growth factor on hepatic stellate cells. Lab Invest. 82, 767–774 (2002).
Gressner, O. A., Lahme, B., Demirci, I., Gressner, A. M. & Weiskirchen, R. Differential effects of TGF-β on connective tissue growth factor (CTGF/CCN2) expression in hepatic stellate cells and hepatocytes. J. Hepatol. 47, 699–710 (2007).
Friedman, S. L. Hepatic stellate cells: protean, multifunctional and enigmatic cells of the liver. Physiol. Rev. 88, 125–172 (2008).
Gressner, O. A. et al. Intracrine signalling of activin A in hepatocytes upregulates connective tissue growth factor (CTGF/CCN2) expression. Liver Int. 28, 1207–1216 (2008).
Fearn, A. et al. The NF-κB1 is a key regulator of acute but not chronic renal injury. Cell Death Dis. 8, e2883 (2017).
Wang, F. et al. NF-κB inhibition alleviates carbon tetrachloride-induced liver fibrosis via suppression of activated hepatic stellate cells. Exp. Ther. Med. 8, 95–99 (2014).
Chan, L. K. et al. Epithelial NEMO/IKK-γ limits fibrosis and promotes regeneration during pancreatitis. Gut 66, 1995–2007 (2017).
Karin, M., Yamamoto, Y. & Wang, Q. M. The IKK NF-κB system: a treasure trove for drug development. Nat. Rev. Drug Discov. 3, 17–26 (2004).
Bennett, J. et al. NF-κB in the crosshairs: rethinking an old riddle. Int. J. Biochem. Cell Biol. 95, 108–112 (2018).
Oakley, F. et al. Inhibition of inhibitor of κB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis. Gastroenterology 128, 108–120 (2005).
Oakley, F. et al. Angiotensin II activates I κB kinase phosphorylation of RelA at Ser 536 to promote myofibroblast survival and liver fibrosis. Gastroenterology 136, 2334–2344 (2009).
Chen, L.-W. et al. The two faces of IKK and NF-κB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia–reperfusion. Nat. Med. 9, 575–581 (2003).
Li, Z.-W. et al. The IKKβ subunit of IκB Kinase (IKK) is essential for nuclear factor κB activation and prevention of apoptosis. J. Exp. Med. 189, 1839–1845 (1999).
Li, Q., Van Antwerp, D., Mercurio, F., Lee, K. F. & Verma, I. M. Severe liver degeneration in mice lacking the IκB kinase 2 gene. Science 284, 321–325 (1999).
Li, Q. & Verma, I. M. NF-κB regulation in the immune system. Nat. Rev. Immunol. 2, 725–734 (2002).
Perkins, N. D. Integrating cell-signalling pathways with NF-κB and IKK function. Nat. Rev. Mol. Cell Biol. 8, 49–62 (2007).
Shono, Y. et al. Characterization of a c-Rel inhibitor that mediates anticancer properties in hematologic malignancies by blocking NF-κB-controlled oxidative stress responses. Cancer Res. 76, 377–389 (2016).
Grinberg-Bleyer, Y. et al. NF-κB c-Rel Is crucial for the regulatory T cell immune checkpoint in cancer. Cell 170, 1096–1108 (2017).
De Bock, K. et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154, 651–663 (2013).
Heise, N. et al. Germinal center B cell maintenance and differentiation are controlled by distinct NF-κB transcription factor subunits. J. Exp. Med. 211, 2103–2118 (2014).
Mederacke, I. et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 4, 2823 (2013).
Higgins, G. A. & Anderson, R. E. Experimental pathology of liver: restoration of liver in white rat following partial surgical removal. Arch. Pathol. 12, 186–202 (1931).
Oakley, F. et al. Nuclear factor-κB1 (p50) limits the inflammatory and fibrogenic responses to chronic injury. Am. J. Pathol. 166, 695–708 (2005).