BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Function of gaseous hydrogen sulfide in liver fibrosis

  • Lee, Jae-Ho (Department of Physiology, Keimyung University School of Medicine) ;
  • Im, Seung-Soon (Department of Physiology, Keimyung University School of Medicine)
  • Received : 2022.07.29
  • Accepted : 2022.09.21
  • Published : 2022.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

Over the past few years, hydrogen sulfide (H2S) has been shown to exert several biological functions in mammalian. The endogenous production of H2S is mainly mediated by cystathione β-synthase, cystathione γ-lyase and 3-mercaptopyruvate sulfur transferase. These enzymes are broadly expressed in liver tissue and regulates liver function by working on a variety of molecular targets. As an important regulator of liver function, H2S is critically involved in the pathogenesis of various liver diseases, such as non-alcoholic steatohepatitis and liver cancer. Targeting H2S-generating enzymes may be a therapeutic strategy for controlling liver diseases. This review described the function of H2S in liver disease and summarized recent characterized role of H2S in several cellular process of the liver.

Keywords

Acknowledgement

This study was supported by the Korea Research Foundation and the NRF grant funded by the Korea Government (MSIP) (NRF-2021R1A4A1029238).

References

  1. Beauchamp RO Jr, Bus JS, Popp JA, Boreiko CJ and Andjelkovich DA (1984) A critical review of the literature on hydrogen sulfide toxicity. Crit Rev Toxicol 13, 25-97 https://doi.org/10.3109/10408448409029321
  2. Wang R (2002) Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J 16, 1792-1798 https://doi.org/10.1096/fj.02-0211hyp
  3. Aroca A, Gotor C and Romero LC (2018) Hydrogen sulfide signaling in plants: emerging roles of protein persulfidation. Front Plant Sci 9, 1369 https://doi.org/10.3389/fpls.2018.01369
  4. Dombkowski RA, Russell MJ and Olson KR (2004) Hydrogen sulfide as an endogenous regulator of vascular smooth muscle tone in trout. Am J Physiol Regul Integr Comp Physiol 286, 678-685
  5. Wojcicka G, Jamroz-Wisniewska A, Atanasova P, Chaldakov GN, Chylinska-Kula B and Beltowski J (2011) Differential effects of statins on endogenous H2S formation in perivascular adipose tissue. Pharmacol Res 63, 68-76 https://doi.org/10.1016/j.phrs.2010.10.011
  6. Abe K and Kimura H (1996) The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 16, 1066-1071 https://doi.org/10.1523/JNEUROSCI.16-03-01066.1996
  7. Kimura H (2002) Hydrogen sulfide as a neuromodulator. Mol Neurobiol 26, 13-19 https://doi.org/10.1385/MN:26:1:013
  8. Li L, Rose P and Moore PK (2011) Hydrogen sulfide and cell signaling. Annu Rev Pharmacol Toxicol 51, 169-187 https://doi.org/10.1146/annurev-pharmtox-010510-100505
  9. Xiao Q, Ying J, Xiang L and Zhang C (2018) The biologic effect of hydrogen sulfide and its function in various diseases. Medicine (Baltimore) 97, e13065 https://doi.org/10.1097/MD.0000000000013065
  10. Han Y, Shang Q, Yao J and Ji Y (2019) Hydrogen sulfide: a gaseous signaling molecule modulates tissue homeostasis: implications in ophthalmic diseases. Cell Death Dis 10, 293 https://doi.org/10.1038/s41419-019-1525-1
  11. Whiteman M and Winyard PG (2011) Hydrogen sulfide and inflammation: the good, the bad, the ugly and the promising. Expert Rev Clin Pharmacol 4, 13-32 https://doi.org/10.1586/ecp.10.134
  12. Bhatia M and Gaddam RR (2021) Hydrogen sulfide in inflammation: a novel mediator and therapeutic target. Antioxid Redox Signal 34, 1368-1377 https://doi.org/10.1089/ars.2020.8211
  13. Ryazantseva NV, Novitsky VV, Starikova EG, Kleptsova LA, Jakushina VD and Kaigorodova EV (2011) Role of hydrogen sulfide in the regulation of cell apoptosis. Bull Exp Biol Med 151, 702-704 https://doi.org/10.1007/s10517-011-1420-y
  14. Li X, Chen M, Shi Q, Zhang H and Xu S (2020) Hydrogen sulfide exposure induces apoptosis and necroptosis through lncRNA3037/miR-15a/BCL2-A20 signaling in broiler trachea. Sci Total Environ 699, 134296 https://doi.org/10.1016/j.scitotenv.2019.134296
  15. Zaichko NV, Melnik AV, Yoltukhivskyy MM, Olhovskiy AS and Palamarchuk IV (2014) Hydrogen sulfide: metabolism, biological and medical role. Ukr Biochem J 86, 5-25
  16. Arif MS, Yasmeen T, Abbas Z et al (2020) Role of exogenous and endogenous hydrogen sulfide (H2S) on functional traits of plants under heavy metal stresses: a recent perspective. Front Plant Sci 11, 545453
  17. Norris EJ, Culberson CR, Narasimhan S and Clemens MG (2011) The liver as a central regulator of hydrogen sulfide. Shock 36, 242-250 https://doi.org/10.1097/SHK.0b013e3182252ee7
  18. Wu DD, Wang DY, Li HM, Guo JC, Duan SF and Ji XY (2019) Hydrogen sulfide as a novel regulatory factor in liver health and disease. Oxid Med Cell Longev 2019, 3831713
  19. Sun HJ, Wu ZY, Nie XW, Wang XY and Bian JS (2021) Implications of hydrogen sulfide in liver pathophysiology: mechanistic insights and therapeutic potential. J Adv Res 27, 127-135 https://doi.org/10.1016/j.jare.2020.05.010
  20. Hellmich MR and Szabo C (2015) Hydrogen sulfide and cancer. Handb Exp Pharmacol 230, 233-241 https://doi.org/10.1007/978-3-319-18144-8_12
  21. Wang SS, Chen YH, Chen N et al (2017) Hydrogen sulfide promotes autophagy of hepatocellular carcinoma cells through the PI3K/Akt/mTOR signaling pathway. Cell Death Dis 8, e2688 https://doi.org/10.1038/cddis.2017.18
  22. Filliol A and Schwabe RF (2019) Contributions of fibroblasts, extracellular matrix, stiffness, and mechanosensing to hepatocarcinogenesis. Semin Liver Dis 39, 315-333 https://doi.org/10.1055/s-0039-1685539
  23. Malone Rubright SL, Pearce LL and Peterson J (2017) Environmental toxicology of hydrogen sulfide. Nitric Oxide 71, 1-13 https://doi.org/10.1016/j.niox.2017.09.011
  24. Doujaiji B and Al-Tawfiq JA (2010) Hydrogen sulfide exposure in an adult male. Ann Saudi Med 30, 76-80 https://doi.org/10.5144/0256-4947.59379
  25. Ahmad A, Gero D, Olah G and Szabo C (2016) Effect of endotoxemia in mice genetically deficient in cystathioninegamma-lyase, cystathionine-beta-synthase or 3-mercaptopyruvate sulfurtransferase. Int J Mol Med 38, 1683-1692 https://doi.org/10.3892/ijmm.2016.2771
  26. Tao B, Wang R, Sun C and Zhu Y (2017) 3-Mercaptopyruvate sulfurtransferase, not cystathionine beta-synthase nor cystathionine gamma-lyase, mediates hypoxia-induced migration of vascular endothelial cells. Front Pharmacol 8, 657 https://doi.org/10.3389/fphar.2017.00657
  27. Ahmad A, Druzhyna N and Szabo C (2019) Effect of 3-mercaptopyruvate sulfurtransferase deficiency on the development of multiorgan failure, inflammation, and wound healing in mice subjected to burn injury. J Burn Care Res 40, 148-156 https://doi.org/10.1093/jbcr/irz007
  28. Augsburger F and Szabo C (2020) Potential role of the 3-mercaptopyruvate sulfurtransferase (3-MST)-hydrogen sulfide (H2S) pathway in cancer cells. Pharmacol Res 154, 104083 https://doi.org/10.1016/j.phrs.2018.11.034
  29. Cao X, Ding L, Xie ZZ et al (2019) A review of hydrogen sulfide synthesis, metabolism, and measurement: is modulation of hydrogen sulfide a novel therapeutic for cancer? Antioxid Redox Signal 31, 1-38 https://doi.org/10.1089/ars.2017.7058
  30. Shibuya N, Koike S, Tanaka M et al (2013) A novel pathway for the production of hydrogen sulfide from D-cysteine in mammalian cells. Nat Commun 4, 1366 https://doi.org/10.1038/ncomms2371
  31. Polhemus DJ and Lefer DJ (2014) Emergence of hydrogen sulfide as an endogenous gaseous signaling molecule in cardiovascular disease. Circ Res 114, 730-737 https://doi.org/10.1161/CIRCRESAHA.114.300505
  32. Murphy B, Bhattacharya R and Mukherjee P (2019) Hydrogen sulfide signaling in mitochondria and disease. FASEB J 33, 13098-13125 https://doi.org/10.1096/fj.201901304R
  33. Pedre B and Dick TP (2021) 3-Mercaptopyruvate sulfurtransferase: an enzyme at the crossroads of sulfane sulfur trafficking. Biol Chem 402, 223-237 https://doi.org/10.1515/hsz-2020-0249
  34. Stipanuk MH and Beck PW (1982) Characterization of the enzymic capacity for cysteine desulphhydration in liver and kidney of the rat. Biochem J 206, 267-277 https://doi.org/10.1042/bj2060267
  35. Nandi SS and Mishra PK (2017) H2S and homocysteine control a novel feedback regulation of cystathionine beta synthase and cystathionine gamma lyase in cardiomyocytes. Sci Rep 7, 3639 https://doi.org/10.1038/s41598-017-03776-9
  36. Cooper AJ (1983) Biochemistry of sulfur-containing amino acids. Annu Rev Biochem 52, 187-222 https://doi.org/10.1146/annurev.bi.52.070183.001155
  37. Hipolito A, Nunes SC, Vicente JB and Serpa J (2020) Cysteine aminotransferase (CAT): a pivotal sponsor in metabolic remodeling and an ally of 3-mercaptopyruvate sulfurtransferase (MST) in cancer. Molecules 25, 3984 https://doi.org/10.3390/molecules25173984
  38. Mikami Y and Kimura H (2012) A mechanism of retinal protection from light-induced degeneration by hydrogen sulfide. Commun Integr Biol 5, 169-171 https://doi.org/10.4161/cib.18679
  39. Guo W, Kan JT, Cheng ZY et al (2012) Hydrogen sulfide as an endogenous modulator in mitochondria and mitochondria dysfunction. Oxid Med Cell Longev 2012, 878052
  40. Wu D, Zheng N, Qi K et al (2015) Exogenous hydrogen sulfide mitigates the fatty liver in obese mice through improving lipid metabolism and antioxidant potential. Med Gas Res 5, 1 https://doi.org/10.1186/s13618-014-0022-y
  41. Wu D, Zhong P, Wang Y et al (2020) Hydrogen sulfide attenuates high-fat diet-induced non-alcoholic fatty liver disease by inhibiting apoptosis and promoting autophagy via reactive oxygen species/phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin signaling pathway. Front Pharmacol 11, 585860 https://doi.org/10.3389/fphar.2020.585860
  42. Comas F and Moreno-Navarrete JM (2021) The impact of H2S on obesity-associated metabolic disturbances. Antioxidants (Basel) 10, 633 https://doi.org/10.3390/antiox10050633
  43. Wang P and Wu L (2018) Hydrogen sulfide and nonalcoholic fatty liver disease. Hepatobiliary Surg Nutr 7, 122-124 https://doi.org/10.21037/hbsn.2018.03.03
  44. Carter RN, Gibbins MTG, Barrios-Llerena ME et al (2021) The hepatic compensatory response to elevated systemic sulfide promotes diabetes. Cell Rep 37, 109958 https://doi.org/10.1016/j.celrep.2021.109958
  45. Pineiro-Ramil M, Burguera EF, Hermida-Gomez T et al (2022) Reduced levels of H2S in diabetes-associated osteoarthritis are linked to hyperglycaemia, Nrf-2/HO-1 signalling downregulation and chondrocyte dysfunction. Antioxidants (Basel) 11, 628 https://doi.org/10.3390/antiox11040628
  46. Gorini F, Del Turco S, Sabatino L, Gaggini M and Vassalle C (2021) H2S as a bridge linking inflammation, oxidative stress and endothelial biology: a possible defense in the fight against SARS-CoV-2 infection? Biomedicines 9, 1107 https://doi.org/10.3390/biomedicines9091107
  47. Jensen-Cody SO and Potthoff MJ (2021) Hepatokines and metabolism: deciphering communication from the liver. Mol Metab 44, 101138 https://doi.org/10.1016/j.molmet.2020.101138
  48. Grant DM (1991) Detoxification pathways in the liver. J Inherit Metab Dis 14, 421-430 https://doi.org/10.1007/BF01797915
  49. Melaram R (2021) Environmental risk factors implicated in liver disease: a mini-review. Front Public Health 9, 683719 https://doi.org/10.3389/fpubh.2021.683719
  50. Tan G, Pan S, Li J et al (2011) Hydrogen sulfide attenuates carbon tetrachloride-induced hepatotoxicity, liver cirrhosis and portal hypertension in rats. PLoS One 6, e25943 https://doi.org/10.1371/journal.pone.0025943
  51. Mateus I and Prip-Buus C (2022) Hydrogen sulphide in liver glucose/lipid metabolism and non-alcoholic fatty liver disease. Eur J Clin Invest 52, e13680 https://doi.org/10.1111/eci.13680
  52. Previte DM, O'Connor EC, Novak EA, Martins CP, Mollen KP and Piganelli JD (2017) Reactive oxygen species are required for driving efficient and sustained aerobic glycolysis during CD4+ T cell activation. PLoS One 12, e0175549 https://doi.org/10.1371/journal.pone.0175549
  53. Snezhkina AV, Kudryavtseva AV, Kardymon OL et al (2019) ROS generation and antioxidant defense systems in normal and malignant cells. Oxid Med Cell Longev 2019, 6175804
  54. Peng HY, Lucavs J, Ballard D et al (2021) Metabolic reprogramming and reactive oxygen species in T cell immunity. Front Immunol 12, 652687 https://doi.org/10.3389/fimmu.2021.652687
  55. Li L, Salto-Tellez M, Tan CH, Whiteman M and Moore PK (2009) GYY4137, a novel hydrogen sulfide-releasing molecule, protects against endotoxic shock in the rat. Free Radic Biol Med 47, 103-113 https://doi.org/10.1016/j.freeradbiomed.2009.04.014
  56. Xia M, Zhang Y, Jin K, Lu Z, Zeng Z and Xiong W (2019) Communication between mitochondria and other organelles: a brand-new perspective on mitochondria in cancer. Cell Biosci 9, 27 https://doi.org/10.1186/s13578-019-0289-8
  57. Brand MD, Orr AL, Perevoshchikova IV and Quinlan CL (2013) The role of mitochondrial function and cellular bioenergetics in ageing and disease. Br J Dermatol 169 Suppl 2, 1-8
  58. Degli Esposti D, Hamelin J, Bosselut N et al (2012) Mitochondrial roles and cytoprotection in chronic liver injury. Biochem Res Int 2012, 387626
  59. Modis K, Coletta C, Erdelyi K, Papapetropoulos A and Szabo C (2013) Intramitochondrial hydrogen sulfide production by 3-mercaptopyruvate sulfurtransferase maintains mitochondrial electron flow and supports cellular bioenergetics. FASEB J 27, 601-611 https://doi.org/10.1096/fj.12-216507
  60. Jia J, Wang Z, Zhang M et al (2020) SQR mediates therapeutic effects of H2S by targeting mitochondrial electron transport to induce mitochondrial uncoupling. Sci Adv 6, eaaz5752 https://doi.org/10.1126/sciadv.aaz5752
  61. Paul BD, Snyder SH and Kashfi K (2021) Effects of hydrogen sulfide on mitochondrial function and cellular bioenergetics. Redox Biol 38, 101772 https://doi.org/10.1016/j.redox.2020.101772
  62. Shimizu Y, Polavarapu R, Eskla KL et al (2018) Hydrogen sulfide regulates cardiac mitochondrial biogenesis via the activation of AMPK. J Mol Cell Cardiol 116, 29-40 https://doi.org/10.1016/j.yjmcc.2018.01.011
  63. Mustafa AK, Gadalla MM, Sen N et al (2009) H2S signals through protein S-sulfhydration. Sci Signal 2, ra72
  64. Modis K, Ju Y, Ahmad A et al (2016) S-Sulfhydration of ATP synthase by hydrogen sulfide stimulates mitochondrial bioenergetics. Pharmacol Res 113, 116-124 https://doi.org/10.1016/j.phrs.2016.08.023
  65. Nuttall FQ, Ngo A and Gannon MC (2008) Regulation of hepatic glucose production and the role of gluconeogenesis in humans: is the rate of gluconeogenesis constant? Diabetes Metab Res Rev 24, 438-458 https://doi.org/10.1002/dmrr.863
  66. Cruz-Pineda WD, Parra-Rojas I, Rodriguez-Ruiz HA, Illades-Aguiar B, Matia-Garcia I and Garibay-Cerdenares OL (2022) The regulatory role of insulin in energy metabolism and leukocyte functions. J Leukoc Biol 111, 197-208
  67. Han HS, Kang G, Kim JS, Choi BH and Koo SH (2016) Regulation of glucose metabolism from a liver-centric perspective. Exp Mol Med 48, e218 https://doi.org/10.1038/emm.2015.122
  68. Irimia JM, Meyer CM, Segvich DM et al (2017) Lack of liver glycogen causes hepatic insulin resistance and steatosis in mice. J Biol Chem 292, 10455-10464 https://doi.org/10.1074/jbc.M117.786525
  69. Manna P, Gungor N, McVie R and Jain SK (2014) Decreased cystathionine-gamma-lyase (CSE) activity in livers of type 1 diabetic rats and peripheral blood mononuclear cells (PBMC) of type 1 diabetic patients. J Biol Chem 289, 11767-11778 https://doi.org/10.1074/jbc.M113.524645
  70. Untereiner AA, Wang R, Ju Y and Wu L (2016) Decreased gluconeogenesis in the absence of cystathionine gamma-lyase and the underlying mechanisms. Antioxid Redox Signal 24, 129-140 https://doi.org/10.1089/ars.2015.6369
  71. Li N, Wang MJ, Jin S et al (2016) The H2S donor NaHS changes the expression pattern of h2s-producing enzymes after myocardial infarction. Oxid Med Cell Longev 2016, 6492469
  72. Dhamija E, Paul SB and Kedia S (2019) Non-alcoholic fatty liver disease associated with hepatocellular carcinoma: an increasing concern. Indian J Med Res 149, 9-17 https://doi.org/10.4103/ijmr.IJMR_1456_17
  73. Rada P, Gonzalez-Rodriguez A, Garcia-Monzon C and Valverde AM (2020) Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver? Cell Death Dis 11, 802 https://doi.org/10.1038/s41419-020-03003-w
  74. Raman M and Allard J (2006) Non alcoholic fatty liver disease: a clinical approach and review. Can J Gastroenterol 20, 345-349 https://doi.org/10.1155/2006/918262
  75. Li M, Xu C, Shi J et al (2018) Fatty acids promote fatty liver disease via the dysregulation of 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide pathway. Gut 67, 2169-2180 https://doi.org/10.1136/gutjnl-2017-313778
  76. Nguyen TTP, Kim DY, Lee YG et al (2021) SREBP-1c impairs ULK1 sulfhydration-mediated autophagic flux to promote hepatic steatosis in high-fat-diet-fed mice. Mol Cell 81, 3820-3832 e3827 https://doi.org/10.1016/j.molcel.2021.06.003
  77. Nguyen TTP, Kim DY, Im SS and Jeon TI (2021) Impairment of ULK1 sulfhydration-mediated lipophagy by SREBF1/SREBP-1c in hepatic steatosis. Autophagy 17, 4489-4490 https://doi.org/10.1080/15548627.2021.1968608
  78. Lan A, Liao X, Mo L et al (2011) Hydrogen sulfide protects against chemical hypoxia-induced injury by inhibiting ROS-activated ERK1/2 and p38MAPK signaling pathways in PC12 cells. PLoS One 6, e25921 https://doi.org/10.1371/journal.pone.0025921
  79. Hine C, Harputlugil E, Zhang Y et al (2015) Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell 160, 132-144 https://doi.org/10.1016/j.cell.2014.11.048
  80. Minamishima S, Bougaki M, Sips PY et al (2009) Hydrogen sulfide improves survival after cardiac arrest and cardiopulmonary resuscitation via a nitric oxide synthase 3-dependent mechanism in mice. Circulation 120, 888-896 https://doi.org/10.1161/CIRCULATIONAHA.108.833491
  81. Jiang T, Yang W, Zhang H, Song Z, Liu T and Lv X (2020) Hydrogen sulfide ameliorates lung ischemiareperfusion injury through SIRT1 signaling pathway in type 2 diabetic rats. Front Physiol 11, 596
  82. Liu H, Bai XB, Shi S and Cao YX (2009) Hydrogen sulfide protects from intestinal ischaemia-reperfusion injury in rats. J Pharm Pharmacol 61, 207-212 https://doi.org/10.1211/jpp.61.02.0010
  83. Sekijima M, Sahara H, Miki K et al (2017) Hydrogen sulfide prevents renal ischemia-reperfusion injury in CLAWN miniature swine. J Surg Res 219, 165-172 https://doi.org/10.1016/j.jss.2017.05.123
  84. Elrod JW, Calvert JW, Morrison J et al (2007) Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc Natl Acad Sci U S A 104, 15560-15565 https://doi.org/10.1073/pnas.0705891104
  85. Takahashi H, Shigefuku R, Yoshida Y et al (2014) Correlation between hepatic blood flow and liver function in alcoholic liver cirrhosis. World J Gastroenterol 20, 17065-17074 https://doi.org/10.3748/wjg.v20.i45.17065
  86. Iwakiri Y, Shah V and Rockey DC (2014) Vascular pathobiology in chronic liver disease and cirrhosis - current status and future directions. J Hepatol 61, 912-924 https://doi.org/10.1016/j.jhep.2014.05.047
  87. Coulouarn C and Clement B (2014) Stellate cells and the development of liver cancer: therapeutic potential of targeting the stroma. J Hepatol 60, 1306-1309 https://doi.org/10.1016/j.jhep.2014.02.003
  88. Zhang F, Jin H, Wu L et al (2017) Diallyl trisulfide suppresses oxidative stress-induced activation of hepatic stellate cells through production of hydrogen sulfide. Oxid Med Cell Longev 2017, 1406726
  89. Damba T, Zhang M, Buist-Homan M, van Goor H, Faber KN and Moshage H (2019) Hydrogen sulfide stimulates activation of hepatic stellate cells through increased cellular bio-energetics. Nitric Oxide 92, 26-33 https://doi.org/10.1016/j.niox.2019.08.004
  90. Wedmann R, Bertlein S, Macinkovic I et al (2014) Working with "H2S": facts and apparent artifacts. Nitric Oxide 41, 85-96 https://doi.org/10.1016/j.niox.2014.06.003
  91. Zheng Y, Ji X, Ji K and Wang B (2015) Hydrogen sulfide prodrugs-a review. Acta Pharm Sin B 5, 367-377 https://doi.org/10.1016/j.apsb.2015.06.004
  92. Xie X, Dai H, Zhuang B, Chai L, Xie Y and Li Y (2016) Exogenous hydrogen sulfide promotes cell proliferation and differentiation by modulating autophagy in human keratinocytes. Biochem Biophys Res Commun 472, 437-443 https://doi.org/10.1016/j.bbrc.2016.01.047
  93. Phillips CM, Zatarain JR, Nicholls ME et al (2017) Upregulation of cystathionine-beta-synthase in colonic epithelia reprograms metabolism and promotes carcinogenesis. Cancer Res 77, 5741-5754
  94. Fan HN, Wang HJ, Yang-Dan CR et al (2013) Protective effects of hydrogen sulfide on oxidative stress and fibrosis in hepatic stellate cells. Mol Med Rep 7, 247-253 https://doi.org/10.3892/mmr.2012.1153
  95. Robert K, Nehme J, Bourdon E et al (2005) Cystathionine beta synthase deficiency promotes oxidative stress, fibrosis, and steatosis in mice liver. Gastroenterology 128, 1405-1415 https://doi.org/10.1053/j.gastro.2005.02.034
  96. Ci L, Yang X, Gu X et al (2017) Cystathionine gammalyase deficiency exacerbates CCl4-Induced acute hepatitis and fibrosis in the mouse liver. Antioxid Redox Signal 27, 133-149 https://doi.org/10.1089/ars.2016.6773
  97. Zhao S, Song T, Gu Y et al (2021) Hydrogen sulfide alleviates liver injury through the S-sulfhydrated-kelchlike ECH-associated protein 1/nuclear erythroid 2-related factor 2/low-density lipoprotein receptor-related protein 1 pathway. Hepatology 73, 282-302 https://doi.org/10.1002/hep.31247
  98. Wang B, Zeng J and Gu Q (2017) Exercise restores bioavailability of hydrogen sulfide and promotes autophagy influx in livers of mice fed with high-fat diet. Can J Physiol Pharmacol 95, 667-674 https://doi.org/10.1139/cjpp-2016-0611
  99. Scammahorn JJ, Nguyen ITN, Bos EM, Van Goor H and Joles JA (2021) Fighting oxidative stress with sulfur: hydrogen sulfide in the renal and cardiovascular systems. Antioxidants (Basel) 10, 373 https://doi.org/10.3390/antiox10030373
  100. Zhang S, Pan C, Zhou F et al (2015) Hydrogen sulfide as a potential therapeutic target in fibrosis. Oxid Med Cell Longev 2015, 593407
  101. Fan HN, Wang HJ, Ren L et al (2013) Decreased expression of p38 MAPK mediates protective effects of hydrogen sulfide on hepatic fibrosis. Eur Rev Med Pharmacol Sci 17, 644-652
  102. Wynn TA and Ramalingam TR (2012) Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 18, 1028-1040 https://doi.org/10.1038/nm.2807
  103. Li XH, Xue WL, Wang MJ et al (2017) H2S regulates endothelial nitric oxide synthase protein stability by promoting microRNA-455-3p expression. Sci Rep 7, 44807 https://doi.org/10.1038/srep44807
  104. Fouad AA, Hafez HM and Hamouda A (2020) Hydrogen sulfide modulates IL-6/STAT3 pathway and inhibits oxidative stress, inflammation, and apoptosis in rat model of methotrexate hepatotoxicity. Hum Exp Toxicol 39, 77-85 https://doi.org/10.1177/0960327119877437
  105. Zeng J, Lin X, Fan H and Li C (2013) Hydrogen sulfide attenuates the inflammatory response in a mouse burn injury model. Mol Med Rep 8, 1204-1208 https://doi.org/10.3892/mmr.2013.1610
  106. Mao YQ and Fan XM (2015) Autophagy: a new therapeutic target for liver fibrosis. World J Hepatol 7, 1982-1986 https://doi.org/10.4254/wjh.v7.i16.1982
  107. Singh KK, Lovren F, Pan Y et al (2015) The essential autophagy gene ATG7 modulates organ fibrosis via regulation of endothelial-to-mesenchymal transition. J Biol Chem 290, 2547-2559 https://doi.org/10.1074/jbc.M114.604603
  108. Lucantoni F, Martinez-Cerezuela A, Gruevska A et al (2021) Understanding the implication of autophagy in the activation of hepatic stellate cells in liver fibrosis: are we there yet? J Pathol 254, 216-228 https://doi.org/10.1002/path.5678
  109. Lv S, Liu H and Wang H (2021) Exogenous hydrogen sulfide plays an important role by regulating autophagy in diabetic-related diseases. Int J Mol Sci 22, 6715 https://doi.org/10.3390/ijms22136715