Table Info

Table 1.

Related drugs targeting FXR

FXR agonists	Alias	Molecular formula	R & D stage	References
Obeticholic acid	6-Ethyl-chenodeoxycholic-acid, OCA	C₂₆H₄₄O₄	Approval to market	[24, 25]
GW4064	GW-4064	C₂₈H₂₂Cl₃NO₄	Preclinical	[24, 25]
Cilofexor	CILO, GS-9674	C₃₂H₃₃Cl₃N₄O₈	Phase III	[24, 25]
Tropifexor	LJN-452, NVP-LJN452-NXA	C₂₉H₂₅F₄N₃O₅S	Phase II	[24, 25]
EDP-305	EDP 305	C₃₆H₅₈N₂O₅S	Phase II	[27]
LY-2562175	None	C₂₈H₂₇Cl₂N₃O₄	Phase II	[24, 25]

Declarations

Author contributions

CW and XY: Writing—review & editing. JW and CZ: Investigation. YZ and CL: Supervision.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by the Science and Technology Research Project of Henan Province [222102310244]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24:908–22. [DOI] [PubMed] [PMC]

Riazi K, Azhari H, Charette JH, Underwood FE, King JA, Afshar EE, et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022;7:851–61. [DOI] [PubMed]

Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2021;18:223–38. [DOI] [PubMed] [PMC]

Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019;380:1450–62. [DOI] [PubMed]

Cao W, Chen HD, Yu YW, Li N, Chen WQ. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J (Engl). 2021;134:783–91. [DOI] [PubMed] [PMC]

Rumgay H, Arnold M, Ferlay J, Lesi O, Cabasag CJ, Vignat J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022;77:1598–606. [DOI] [PubMed] [PMC]

Saraiya N, Yopp AC, Rich NE, Odewole M, Parikh ND, Singal AG. Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy. Aliment Pharmacol Ther. 2018;48:127–37. [DOI] [PubMed] [PMC]

Ioannou GN. Epidemiology and risk-stratification of NAFLD-associated HCC. J Hepatol. 2021;75:1476–84. [DOI] [PubMed]

Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet. 2022;400:1345–62. [DOI] [PubMed]

10.

Foerster F, Gairing SJ, Muller L, Galle PR. NAFLD-driven HCC: safety and efficacy of current and emerging treatment options. J Hepatol. 2022;76:446–57. [DOI] [PubMed]

11.

Yang YL, Wang PW, Wang FS, Lin HY, Huang YH. MiR-29a modulates GSK3β/SIRT1-linked mitochondrial proteostatic stress to ameliorate mouse non-alcoholic steatohepatitis. Int J Mol Sci. 2020;21:6884. [DOI] [PubMed] [PMC]

12.

Nassir F. NAFLD: mechanisms, treatments, and biomarkers. Biomolecules. 2022;12:824. [DOI] [PubMed] [PMC]

13.

Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65:1038–48. [DOI] [PubMed]

14.

Bernal-Reyes R, Castro-Narro G, Malé-Velázquez R, Carmona-Sánchez R, González-Huezo MS, García-Juárez I, et al. The mexican consensus on nonalcoholic fatty liver disease. Rev Gastroenterol Mex (Engl Ed). 2019;84:69–99. English, Spanish. [DOI] [PubMed]

15.

Sakurai Y, Kubota N, Yamauchi T, Kadowaki T. Role of insulin resistance in MAFLD. Int J Mol Sci. 2021;22:4156. [DOI] [PubMed] [PMC]

16.

Ding X, Jian T, Li J, Lv H, Tong B, Li J, et al. Chicoric acid ameliorates nonalcoholic fatty liver disease via the AMPK/Nrf2/NFκB signaling pathway and restores gut microbiota in high-fat-diet-fed mice. Oxid Med Cell Longev. 2020;2020:9734560. [DOI] [PubMed] [PMC]

17.

Chen Z, Tian R, She Z, Cai J, Li H. Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease. Free Radic Biol Med. 2020;152:116–41. [DOI] [PubMed]

18.

Gonzalez A, Huerta-Salgado C, Orozco-Aguilar J, Aguirre F, Tacchi F, Simon F, et al. Role of oxidative stress in hepatic and extrahepatic dysfunctions during nonalcoholic fatty liver disease (NAFLD). Oxid Med Cell Longev. 2020;2020:1617805. [DOI] [PubMed] [PMC]

19.

Yang Y, Zhao Y, Li W, Wu Y, Wang X, Wang Y, et al. Emerging targets and potential therapeutic agents in non-alcoholic fatty liver disease treatment. Eur J Med Chem. 2020;197:112311. [DOI] [PubMed]

20.

Tardelli M, Claudel T, Bruschi FV, Trauner M. Nuclear receptor regulation of aquaglyceroporins in metabolic organs. Int J Mol Sci. 2018;19:1777. [DOI] [PubMed] [PMC]

21.

Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013;17:225–35. [DOI] [PubMed]

22.

Karasawa K, Tanigawa K, Harada A, Yamashita A. Transcriptional regulation of acyl-CoA:glycerol-sn-3-phosphate acyltransferases. Int J Mol Sci. 2019;20:964. [DOI] [PubMed] [PMC]

23.

Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, et al. 6α-Ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002;45:3569–72. [DOI] [PubMed]

24.

Kremoser C. FXR agonists for NASH: how are they different and what difference do they make? J Hepatol. 2021;75:12–5. [DOI] [PubMed]

25.

Li J, Liu M, Li Y, Sun DD, Shu Z, Tan Q, et al. Discovery and optimization of non-bile acid FXR agonists as preclinical candidates for the treatment of nonalcoholic steatohepatitis. J Med Chem. 2020;63:12748–72. [DOI] [PubMed]

26.

Attia SL, Softic S, Mouzaki M. Evolving role for pharmacotherapy in NAFLD/NASH. Clin Transl Sci. 2021;14:11–9. [DOI] [PubMed] [PMC]

27.

Fiorucci S, Biagioli M, Sepe V, Zampella A, Distrutti E. Bile acid modulators for the treatment of nonalcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 2020;29:623–32. [DOI] [PubMed]

28.

Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347:645–50. [DOI] [PubMed]

29.

Manoharan I, Suryawanshi A, Hong Y, Ranganathan P, Shanmugam A, Ahmad S, et al. Homeostatic PPARα signaling limits inflammatory responses to commensal microbiota in the intestine. J Immunol. 2016;196:4739–49. [DOI] [PubMed] [PMC]

30.

Boyer-Diaz Z, Aristu-Zabalza P, Andres-Rozas M, Robert C, Ortega-Ribera M, Fernandez-Iglesias A, et al. Pan-PPAR agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease. J Hepatol. 2021;74:1188–99. [DOI] [PubMed]

31.

Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z, et al. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem. 1998;273:25573–80. [DOI] [PubMed]

32.

Shizu R, Otsuka Y, Ishii C, Ezaki K, Yoshinari K. PPARα induces the expression of CAR that works as a negative regulator of PPARα functions in mouse livers. Int J Mol Sci. 2023;24:3953. [DOI] [PubMed] [PMC]

33.

Francque S, Verrijken A, Caron S, Prawitt J, Paumelle R, Derudas B, et al. PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J Hepatol. 2015;63:164–73. [DOI] [PubMed]

34.

Mahmoudi A, Jamialahmadi T, Johnston TP, Sahebkar A. Impact of fenofibrate on NAFLD/NASH: a genetic perspective. Drug Discov Today. 2022;27:2363–72. [DOI] [PubMed]

35.

Fatani S, Itua I, Clark P, Wong C, Naderali EK. The effects of diet-induced obesity on hepatocyte insulin signaling pathways and induction of non-alcoholic liver damage. Int J Gen Med. 2011;4:211–9. [DOI] [PubMed] [PMC]

36.

Yamashita S, Masuda D, Matsuzawa Y. Pemafibrate, a new selective PPARα modulator: drug concept and its clinical applications for dyslipidemia and metabolic diseases. Curr Atheroscler Rep. 2020;22:5. [DOI] [PubMed] [PMC]

37.

Zhang X, Wang S, Hu L, Wang J, Liu Y, Shi P. Gemfibrozil reduces lipid accumulation in SMMC-7721 cells via the involvement of PPARα and SREBP1. Exp Ther Med. 2019;17:1282–9. [DOI] [PubMed] [PMC]

38.

Boeckmans J, Natale A, Rombaut M, Buyl K, Cami B, De Boe V, et al. Human hepatic in vitro models reveal distinct anti-NASH potencies of PPAR agonists. Cell Biol Toxicol. 2021;37:293–311. [DOI] [PubMed]

39.

Sasaki Y, Asahiyama M, Tanaka T, Yamamoto S, Murakami K, Kamiya W, et al. Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content. Sci Rep. 2020;10:7818. [DOI] [PubMed] [PMC]

40.

Wagner N, Wagner KD. The role of PPARs in disease. Cells. 2020;9:2367. [DOI] [PubMed] [PMC]

41.

Xiao L, Wang N. PPAR-δ: a key nuclear receptor in vascular function and remodeling. J Mol Cell Cardiol. 2022;169:1–9. [DOI] [PubMed]

42.

Haczeyni F, Wang H, Barn V, Mridha AR, Yeh MM, Haigh WG, et al. The selective peroxisome proliferator-activated receptor-delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice. Hepatol Commun. 2017;1:663–74. [DOI] [PubMed] [PMC]

43.

Westerouen Van Meeteren MJ, Drenth JPH, Tjwa ETTL. Elafibranor: a potential drug for the treatment of nonalcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 2020;29:117–23. [DOI] [PubMed]

44.

Heitel P, Faudone G, Helmstadter M, Schmidt J, Kaiser A, Tjaden A, et al. A triple farnesoid X receptor and peroxisome proliferator-activated receptor α/δ activator reverses hepatic fibrosis in diet-induced NASH in mice. Commun Chem. 2020;3:174. [DOI] [PubMed] [PMC]

45.

Gul F, Parvaiz N, Azam SS. Deciphering the relational dynamics of AF-2 domain of PAN PPAR through drug repurposing and comparative simulations. PLoS One. 2023;18:e0283743. [DOI] [PubMed] [PMC]

46.

Romero FA, Jones CT, Xu Y, Fenaux M, Halcomb RL. The race to bash NASH: emerging targets and drug development in a complex liver disease. J Med Chem. 2020;63:5031–73. [DOI] [PubMed]

47.

Skat-Rørdam J, Højland Ipsen D, Lykkesfeldt J, Tveden-Nyborg P. A role of peroxisome proliferator-activated receptor γ in non-alcoholic fatty liver disease. Basic Clin Pharmacol Toxicol. 2019;124:528–37. [DOI] [PubMed] [PMC]

48.

Takada I, Makishima M. Peroxisome proliferator-activated receptor agonists and antagonists: a patent review (2014–present). Expert Opin Ther Pat. 2020;30:1–13. [DOI] [PubMed]

49.

Wang L, Waltenberger B, Pferschy-Wenzig EM, Blunder M, Liu X, Malainer C, et al. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review. Biochem Pharmacol. 2014;92:73–89. [DOI] [PubMed] [PMC]

50.

Gawrieh S, Noureddin M, Loo N, Mohseni R, Awasty V, Cusi K, et al. Saroglitazar, a PPAR-α/γ agonist, for treatment of NAFLD: a randomized controlled double-blind phase 2 trial. Hepatology. 2021;74:1809–24. [DOI] [PubMed]

51.

Perakakis N, Joshi A, Peradze N, Stefanakis K, Li G, Feigh M, et al. The selective peroxisome proliferator-activated receptor gamma modulator CHS-131 improves liver histopathology and metabolism in a mouse model of obesity and nonalcoholic steatohepatitis. Hepatol Commun. 2020;4:1302–15. [DOI] [PubMed] [PMC]

52.

Flippo KH, Potthoff MJ. Metabolic messengers: FGF21. Nat Metab. 2021;3:309–17. [DOI] [PubMed] [PMC]

53.

Dushay J, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M, Fisher FM, et al. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology. 2010;139:456–63. [DOI] [PubMed] [PMC]

54.

Yano K, Yamaguchi K, Seko Y, Okishio S, Ishiba H, Tochiki N, et al. Hepatocyte-specific fibroblast growth factor 21 overexpression ameliorates high-fat diet-induced obesity and liver steatosis in mice. Lab Invest. 2022;102:281–9. [DOI] [PubMed]

55.

Foltz IN, Hu S, King C, Wu X, Yang C, Wang W, et al. Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex. Sci Transl Med. 2012;4:162ra153. [DOI] [PubMed]

56.

Zarei M, Pizarro-Delgado J, Barroso E, Palomer X. Vazquez-Carrera M. Targeting FGF21 for the treatment of nonalcoholic steatohepatitis. Trends Pharmacol Sci. 2020;41:199–208. [DOI] [PubMed]

57.

Kharitonenkov A, Adams AC. Inventing new medicines: the FGF21 story. Mol Metab. 2014;3:221–9. [DOI] [PubMed] [PMC]

58.

Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 2013;18:333–40. [DOI] [PubMed]

59.

So WY, Leung PS. Fibroblast growth factor 21 as an emerging therapeutic target for type 2 diabetes mellitus. Med Res Rev. 2016;36:672–704. [DOI] [PubMed]

60.

Liu X, Wang K, Wang L, Kong L, Hou S, Wan Y, et al. Hepatocyte leukotriene B4 receptor 1 promotes NAFLD development in obesity. Hepatology. 2023;78:562–77. [DOI] [PubMed]

61.

Powell EE, Wong VW, Rinella M. Non-alcoholic fatty liver disease. Lancet. 2021;397:2212–24. [DOI] [PubMed]

62.

Liu Z, Zhang Y, Graham S, Wang X, Cai D, Huang M, et al. Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping. J Hepatol. 2020;73:263–76. [DOI] [PubMed] [PMC]

63.

Marengo A, Rosso C, Bugianesi E. Liver cancer: connections with obesity, fatty liver, and cirrhosis. Annu Rev Med. 2016;67:103–17. [DOI] [PubMed]

64.

Kim H, Lee DS, An TH, Park HJ, Kim WK, Bae KH, et al. Metabolic spectrum of liver failure in type 2 diabetes and obesity: from NAFLD to NASH to HCC. Int J Mol Sci. 2021;22;4495. [DOI] [PubMed] [PMC]

65.

Kim I, Morimura K, Shah Y, Yang Q, Ward JM, Gonzalez FJ. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis. 2007;28:940–6. [DOI] [PubMed] [PMC]

66.

Sun L, Cai J, Gonzalez FJ. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat Rev Gastroenterol Hepatol. 2021;18:335–47. [DOI] [PubMed]

67.

Liu N, Meng Z, Lou G, Zhou W, Wang X, Zhang Y, et al. Hepatocarcinogenesis in FXR^–/– mice mimics human HCC progression that operates through HNF1α regulation of FXR expression. Mol Endocrinol. 2012;26:775–85. [DOI] [PubMed] [PMC]

68.

Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301–14. [DOI] [PubMed]

69.

Ferrebee CB, Dawson PA. Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids. Acta Pharm Sin B. 2015;5:129–34. [DOI] [PubMed] [PMC]

70.

Paul B, Lewinska M, Andersen JB. Lipid alterations in chronic liver disease and liver cancer. JHEP Rep. 2022;4:100479. [DOI] [PubMed] [PMC]

71.

Zeng W, Yin X, Jiang Y, Jin L, Liang W. PPARα at the crossroad of metabolic-immune regulation in cancer. FEBS J. 2022;289:7726–39. [DOI] [PubMed]

72.

Zhang N, Chu ES, Zhang J, Li X, Liang Q, Chen J, et al. Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-κB signaling pathway. Oncotarget. 2014;5:8330–40. [DOI] [PubMed] [PMC]

73.

Van Ginderachter JA, Movahedi K, Van den Bossche J, De Baetselier P. Macrophages, PPARs, and cancer. PPAR Res. 2008;2008:169414. [DOI] [PubMed] [PMC]

74.

Balandaram G, Kramer LR, Kang BH, Murray IA, Perdew GH, Gonzalez FJ, et al. Ligand activation of peroxisome proliferator-activated receptor-β/δ suppresses liver tumorigenesis in hepatitis B transgenic mice. Toxicology. 2016;363-364:1–9. [DOI] [PubMed] [PMC]

75.

Xu L, Han C, Lim K, Wu T. Cross-talk between peroxisome proliferator-activated receptor δ and cytosolic phospholipase A₂α/cyclooxygenase-2/prostaglandin E₂ signaling pathways in human hepatocellular carcinoma cells. Cancer Res. 2006;66:11859–68. [DOI] [PubMed]

76.

Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α): transcriptional coactivator and metabolic regulator. Endocr Rev. 2003;24:78–90. [DOI] [PubMed] [PMC]

77.

Li MY, Lee TW, Yim AP, Chen GG. Function of PPARγ and its ligands in lung cancer. Crit Rev Clin Lab Sci. 2006;43:183–202. [DOI] [PubMed]

78.

Bo QF, Sun XM, Liu J, Sui XM, Li GX. Antitumor action of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone in hepatocellular carcinoma. Oncol Lett. 2015;10:1979–84. [DOI] [PubMed] [PMC]

79.

Lu W, Li X, Luo Y. FGF21 in obesity and cancer: new insights. Cancer Lett. 2021;499:5–13. [DOI] [PubMed] [PMC]

80.

Falamarzi K, Malekpour M, Tafti MF, Azarpira N, Behboodi M, Zarei M. The role of FGF21 and its analogs on liver associated diseases. Front Med (Lausanne). 2022;9:967375. [DOI] [PubMed] [PMC]

81.

Yang C, Lu W, Lin T, You P, Ye M, Huang Y, et al. Activation of liver FGF21 in hepatocarcinogenesis and during hepatic stress. BMC Gastroenterol. 2013;13:67. [DOI] [PubMed] [PMC]

82.

Zhang F, Yu L, Lin X, Cheng P, He L, Li X, et al. Minireview: roles of fibroblast growth factors 19 and 21 in metabolic regulation and chronic diseases. Mol Endocrinol. 2015;29:1400–13. [DOI] [PubMed] [PMC]

83.

Huang X, Yu C, Jin C, Yang C, Xie R, Cao D, et al. Forced expression of hepatocyte-specific fibroblast growth factor 21 delays initiation of chemically induced hepatocarcinogenesis. Mol Carcinog. 2006;45:934–42. [DOI] [PubMed]