Exploration of Digestive Diseases

From: Searching for novel cellular targets for MASLD and HCC within the humble lysosomal cathepsins

Table 1. Biological roles of cathepsins during MASLD/MASH and HCC development and progression

Type	Name and MEROPS ID	Biomarker role	MASLD/MASH	HCC
Aspartate	Cathepsin D (A01.009)	Serum levels correlate with MASH and insulin resistance in human [42, 43] Tumour expression and serum levels may be diagnostic and prognostic markers for HCC [56]	FFA flux regulation between mitochondria and cytoplasmic compartment [26] Regulation of systemic inflammation and hepatic inflammatory gene expression [39, 44] Regulation of hepatic lipid accumulation and cholesterol metabolism [39, 44]	Regulation of tumour cell proliferation via IGF-1 signalling pathway [67, 68] Regulation of apoptosis cleaving Bid [75] Promotion of migration and invasiveness [84] Immunosuppressive TAM phenotype regulation [94]
Cysteine	Cathepsin B (C01.060)	Expression in tumour as a marker of HCC and bad prognosis [55]	FFA flux regulation between mitochondria and cytoplasmic compartment [25] Regulation of hepatic lipid accumulation and de novo lipogenesis [36] Induction of M1 phenotype in macrophages [36] Regulation of hepatic inflammation via NF-κB dependent gene expression [37] and inflammasome [38, 41]	Regulation of tumour cell proliferation via PI3K/AKT [66] and IGF-1 [69] Regulation of apoptosis cleaving Bid [71, 74] Promotion of tumour migration and invasiveness [55, 81–84] Regulation of angiogenesis [82] Immunosuppressive TAM phenotype regulation [92, 93]
	Cathepsin C (C01.070)	-	-	Promotion of metastasis via activation of TNF-α/p38 MAPK [85]
	Cathepsin H (C01.040)	-	-	Contribution to radioresistance inhibiting apoptosis [80]
	Cathepsin K (C01.036)	Expression in tumour as a marker of HCC [61]	-	Regulation of tumour cell proliferation via PI3K/AKT [61]
	Cathepsin L (C01.032)	Expression in tumour as a marker of HCC and bad prognosis [60]	Regulation of hepatic inflammation via inflammasome activation [40]	Regulation of tumour growth [60] Inhibition of cancer cell motility [87] Immunosuppressive TAM phenotype regulation [93]
	Cathepsin S (C01.034)	Expression in tumour as a marker of HCC [59]	Regulation of hepatic inflammation via inflammasome activation [40]	Regulation of tumour cell proliferation [70] Inhibition of cancer cell apoptosis and contribution to chemoresistance [76] Promotion of metastasis via activation of VEGF-A/MEK1/ERK1/2 signalling [86] Regulation of angiogenesis [70, 86] Immunosuppressive TAM phenotype regulation [92, 93]
	Cathepsin L2/V/U (C01.009)	Expression in tumour as a marker of HCC and bad prognosis [63]	-	Regulation of tumour cell proliferation [63]
	Cathepsin X/Z (C01.013)	Expression in tumour as a marker of HCC [64]	-	Regulation of epithelial-to-mesenchymal transition and metastatic potential [64]
Serine	Cathepsin A (S10.002)	Tumour expression and serum levels may be diagnostic and prognostic markers for HCC [57, 58, 65]	-	-
Serine	Cathepsin G (S01.133)	Expression in tumour as a marker of HCC [62]	-	-

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MASLD: metabolic-associated steatotic liver disease; MASH: metabolic dysfunction-associated steatohepatitis; HCC: hepatocellular carcinoma; FFA: free fatty acids; IGF-1: insulin-like growth factor 1; TAM: tumour-associated macrophage

Declarations

Author contributions

AdCC and MFF: Writing—original draft. AM: Conceptualization, Visualization, Writing—original draft, Writing—review & editing.

Conflicts of interest

The authors have no conflict of interest to disclose.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

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Availability of data and materials

Not applicable.

Funding

This work was funded by MCIN/AEI/10.13039/501100011033/FEDER, UE through the project grants [PID2021-123652OB-I00] and [RTI2018-097475-A-100] (AM); by MCIN/AEI/10.13039/501100011033 and El FSE invest in your future through the contract [RYC-2016-19731] (AM); by Pfizer grant [#77131383] (AM); by CSIC contract [JAEINT_23_01245] (AdCC); and by Ministerio de Universidades, Spain contract [FPU20/01367] (MFF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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References

Wang F, Gómez-Sintes R, Boya P. Lysosomal membrane permeabilization and cell death. Traffic. 2018;19:918–31. [DOI] [PubMed]

Perera RM, Zoncu R. The Lysosome as a Regulatory Hub. Annu Rev Cell Dev Biol. 2016;32:223–53. [DOI] [PubMed] [PMC]

Ballabio A, Bonifacino JS. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol Cell Biol. 2020;21:101–18. [DOI] [PubMed]

Settembre C, Perera RM. Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology. Nat Rev Mol Cell Biol. 2024;25:223–45. [DOI] [PubMed]

Müller S, Dennemärker J, Reinheckel T. Specific functions of lysosomal proteases in endocytic and autophagic pathways. Biochim Biophys Acta. 2012;1824:34–43. [DOI] [PubMed] [PMC]

Mason SD, Joyce JA. Proteolytic networks in cancer. Trends Cell Biol. 2011;21:228–37. [DOI] [PubMed] [PMC]

Wolters PJ, Chapman HA. Importance of lysosomal cysteine proteases in lung disease. Respir Res. 2000;1:170–7. [DOI] [PubMed] [PMC]

Sampognaro PJ, Arya S, Knudsen GM, Gunderson EL, Sandoval-Perez A, Hodul M, et al. Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases. Mol Neurodegener. 2023;18:29. [DOI] [PubMed] [PMC]

van Kasteren SI, Overkleeft HS. Endo-lysosomal proteases in antigen presentation. Curr Opin Chem Biol. 2014;23:8–15. [DOI] [PubMed]

10.

De Pasquale V, Moles A, Pavone LM. Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy. Cells. 2020;9:979. [DOI] [PubMed] [PMC]

11.

Hartley BS. Proteolytic enzymes. Annu Rev Biochem. 1960;29:45–72. [DOI] [PubMed]

12.

Rawlings ND, Barrett AJ, Bateman A. MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res. 2012;40:D343–50. [DOI] [PubMed] [PMC]

13.

Talukdar R, Sareen A, Zhu H, Yuan Z, Dixit A, Cheema H, et al. Release of Cathepsin B in Cytosol Causes Cell Death in Acute Pancreatitis. Gastroenterology. 2016;151:747–58.e5. [DOI] [PubMed] [PMC]

14.

Tamhane T, Lllukkumbura R, Lu S, Maelandsmo GM, Haugen MH, Brix K. Nuclear cathepsin L activity is required for cell cycle progression of colorectal carcinoma cells. Biochimie. 2016;122:208–18. [DOI] [PubMed]

15.

Ochieng J, Chaudhuri G. Cystatin superfamily. J Health Care Poor Underserved. 2010;21:51–70. [DOI] [PubMed] [PMC]

16.

Ii K, Hizawa K, Kominami E, Bando Y, Katunuma N. Different immunolocalizations of cathepsins B, H, and L in the liver. J Histochem Cytochem. 1985;33:1173–5. [DOI] [PubMed]

17.

Grinde B. Autophagy and lysosomal proteolysis in the liver. Experientia. 1985;41:1089–95. [DOI] [PubMed]

18.

Ishisaka R, Kanno T, Akiyama J, Yoshioka T, Utsumi K, Utsumi T. Activation of caspase-3 by lysosomal cysteine proteases and its role in 2,2’-azobis-(2-amidinopropane)dihydrochloride (AAPH)-induced apoptosis in HL-60 cells. J Biochem. 2001;129:35–41. [DOI] [PubMed]

19.

Roberts LR, Adjei PN, Gores GJ. Cathepsins as effector proteases in hepatocyte apoptosis. Cell Biochem Biophys. 1999;30:71–88. [DOI] [PubMed]

20.

Ruiz-Blázquez P, Pistorio V, Fernández-Fernández M, Moles A. The multifaceted role of cathepsins in liver disease. J Hepatol. 2021;75:1192–202. [DOI] [PubMed]

21.

Moles A, Tarrats N, Fernández-Checa JC, Marí M. Cathepsins B and D drive hepatic stellate cell proliferation and promote their fibrogenic potential. Hepatology. 2009;49:1297–307. [DOI] [PubMed] [PMC]

22.

van Mourik H, Li M, Baumgartner S, Theys J, Shiri-Sverdlov R. All Roads Lead to Cathepsins: The Role of Cathepsins in Non-Alcoholic Steatohepatitis-Induced Hepatocellular Carcinoma. Biomedicines. 2022;10:2351. [DOI] [PubMed] [PMC]

23.

Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11–20. [DOI] [PubMed]

24.

E Martini, MU Dianzani. Activation of cathepsin in fatty liver. Experientia. 1958;14:285–6. [DOI] [PubMed]

25.

Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem. 2006;281:12093–101. [DOI] [PubMed]

26.

Hamlin AN, Basford JE, Jaeschke A, Hui DY. LRP1 Protein Deficiency Exacerbates Palmitate-induced Steatosis and Toxicity in Hepatocytes. J Biol Chem. 2016;291:16610–9. [DOI] [PubMed] [PMC]

27.

Fukuo Y, Yamashina S, Sonoue H, Arakawa A, Nakadera E, Aoyama T, et al. Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease. Hepatol Res. 2014;44:1026–36. [DOI] [PubMed]

28.

Wang X, Zhang X, Chu ESH, Chen X, Kang W, Wu F, et al. Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis. FASEB J. 2018;32:37–51. [DOI] [PubMed]

29.

Chi WY, Lee GH, Tang MJ, Chen BH, Lin WL, Fu TF. Disturbed intracellular folate homeostasis impairs autophagic flux and increases hepatocytic lipid accumulation. BMC Biol. 2024;22:146. [DOI] [PubMed] [PMC]

30.

Kim HJ, Han YH, Kim JY, Lee MO. RORα Enhances Lysosomal Acidification and Autophagic Flux in the Hepatocytes. Hepatol Commun. 2021;5:2121–38. [DOI] [PubMed] [PMC]

31.

Yan S. Role of TFEB in Autophagy and the Pathogenesis of Liver Diseases. Biomolecules. 2022;12:672. [DOI] [PubMed] [PMC]

32.

Fang Y, Ji L, Zhu C, Xiao Y, Zhang J, Lu J, et al. Liraglutide Alleviates Hepatic Steatosis by Activating the TFEB-Regulated Autophagy-Lysosomal Pathway. Front Cell Dev Biol. 2020;8:602574. [DOI] [PubMed] [PMC]

33.

Matye D, Gunewardena S, Chen J, Wang H, Wang Y, Hasan MN, et al. TFEB regulates sulfur amino acid and coenzyme A metabolism to support hepatic metabolic adaptation and redox homeostasis. Nat Commun. 2022;13:5696. [DOI] [PubMed] [PMC]

34.

Mizunoe Y, Kobayashi M, Tagawa R, Nakagawa Y, Shimano H, Higami Y. Association between Lysosomal Dysfunction and Obesity-Related Pathology: A Key Knowledge to Prevent Metabolic Syndrome. Int J Mol Sci. 2019;20:3688. [DOI] [PubMed] [PMC]

35.

Li H, Zhou Y, Wang H, Zhang M, Qiu P, Zhang M, et al. Crosstalk Between Liver Macrophages and Surrounding Cells in Nonalcoholic Steatohepatitis. Front Immunol. 2020;11:1169. [DOI] [PubMed] [PMC]

36.

Fang W, Deng Z, Benadjaoud F, Yang C, Shi GP. Cathepsin B deficiency ameliorates liver lipid deposition, inflammatory cell infiltration, and fibrosis after diet-induced nonalcoholic steatohepatitis. Transl Res. 2020;222:28–40. [DOI] [PubMed] [PMC]

37.

de Mingo Á, de Gregorio E, Moles A, Tarrats N, Tutusaus A, Colell A, et al. Cysteine cathepsins control hepatic NF-κB-dependent inflammation via sirtuin-1 regulation. Cell Death Dis. 2016;7:e2464. [DOI] [PubMed] [PMC]

38.

Tang Y, Cao G, Min X, Wang T, Sun S, Du X, et al. Cathepsin B inhibition ameliorates the non-alcoholic steatohepatitis through suppressing caspase-1 activation. J Physiol Biochem. 2018;74:503–10. [DOI] [PubMed]

39.

Houben T, Oligschlaeger Y, Hendrikx T, Bitorina AV, Walenbergh SMA, van Gorp PJ, et al. Cathepsin D regulates lipid metabolism in murine steatohepatitis. Sci Rep. 2017;7:3494. [DOI] [PubMed] [PMC]

40.

Campden RI, Zhang Y. The role of lysosomal cysteine cathepsins in NLRP3 inflammasome activation. Arch Biochem Biophys. 2019;670:32–42. [DOI] [PubMed]

41.

Zuo R, Ye LF, Huang Y, Song ZQ, Wang L, Zhi H, et al. Hepatic small extracellular vesicles promote microvascular endothelial hyperpermeability during NAFLD via novel-miRNA-7. J Nanobiotechnology. 2021;19:396. [DOI] [PubMed] [PMC]

42.

Walenbergh SM, Houben T, Rensen SS, Bieghs V, Hendrikx T, van Gorp PJ, et al. Plasma cathepsin D correlates with histological classifications of fatty liver disease in adults and responds to intervention. Sci Rep. 2016;6:38278. [DOI] [PubMed] [PMC]

43.

Ding L, De Munck TJI, Oligschlaeger Y, Verbeek J, Koek GH, Houben T, et al. Insulin resistance is positively associated with plasma cathepsin D activity in NAFLD patients. Biomol Concepts. 2021;12:110–5. [DOI] [PubMed]

44.

Yadati T, Houben T, Bitorina A, Oligschlaeger Y, Gijbels MJ, Mohren R, et al. Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice. Front Immunol. 2021;12:675535. [DOI] [PubMed] [PMC]

45.

Canbay A, Guicciardi ME, Higuchi H, Feldstein A, Bronk SF, Rydzewski R, et al. Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis. J Clin Invest. 2003;112:152–9. [DOI] [PubMed] [PMC]

46.

Ruiz-Blázquez P, Fernández-Fernández M, Pistorio V, Martinez-Sanchez C, Costanzo M, Iruzubieta P, et al. Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis. Mol Metab. 2024;87:101989. [DOI] [PubMed]

47.

Fernández-Fernández M, Ruiz-Blázquez P, Cacho-Pujol J, Moles A. Lysosomal hydrolases, from waste-bags effectors to essential multipurpose enzymes in liver fibrosis. Explor Dig Dis. 2023;2:1–10. [DOI]

48.

Karim G, Bansal MB. Resmetirom: An Orally Administered, Smallmolecule, Liver-directed, β-selective THR Agonist for the Treatment of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis. touchREV Endocrinol. 2023;19:60–70. [DOI] [PubMed] [PMC]

49.

Harrison SA, Taub R, Neff GW, Lucas KJ, Labriola D, Moussa SE, et al. Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial. Nat Med. 2023;29:2919–28. [DOI] [PubMed] [PMC]

50.

Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, et al.; MAESTRO-NASH Investigators. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024;390:497–509. [DOI] [PubMed]

51.

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

52.

Calderon-Martinez E, Landazuri-Navas S, Vilchez E, Cantu-Hernandez R, Mosquera-Moscoso J, Encalada S, et al. Prognostic Scores and Survival Rates by Etiology of Hepatocellular Carcinoma: A Review. J Clin Med Res. 2023;15:200–7. [DOI] [PubMed] [PMC]

53.

Kanwal F, Kramer JR, Mapakshi S, Natarajan Y, Chayanupatkul M, Richardson PA, et al. Risk of Hepatocellular Cancer in Patients With Non-Alcoholic Fatty Liver Disease. Gastroenterology. 2018;155:1828–37.e2. [DOI] [PubMed] [PMC]

54.

Younossi Z, Stepanova M, Ong JP, Jacobson IM, Bugianesi E, Duseja A, et al. Nonalcoholic Steatohepatitis Is the Fastest Growing Cause of Hepatocellular Carcinoma in Liver Transplant Candidates. Clin Gastroenterol Hepatol. 2019;17:748–55.e3. [DOI] [PubMed]

55.

Ruan J, Zheng H, Rong X, Rong X, Zhang J, Fang W, et al. Over-expression of cathepsin B in hepatocellular carcinomas predicts poor prognosis of HCC patients. Mol Cancer. 2016;15:17. [DOI] [PubMed] [PMC]

56.

Chuaypen N, Sriphoosanaphan S, Vorasittha A, Pinjaroen N, Chaiyarit S, Thongboonkerd V, et al. Targeted Proteins Reveal Cathepsin D as a Novel Biomarker in Differentiating Hepatocellular Carcinoma from Cirrhosis and Other Liver Cancers. Asian Pac J Cancer Prev. 2022;23:2017–25. [DOI] [PubMed] [PMC]

57.

Wang H, Xu F, Yang F, Lv L, Jiang Y. Prognostic significance and oncogene function of cathepsin A in hepatocellular carcinoma. Sci Rep. 2021;11:14611. [DOI] [PubMed] [PMC]

58.

Luo L, Wang X, Wang H, Yang C, Zhang Y, Li X, et al. High cathepsin A protein expression predicts poor prognosis and tumor recurrence of hepatocellular carcinoma patients after curative hepatectomy. Am J Cancer Res. 2022;12:3843–56. [PubMed] [PMC]

59.

Xu J, Li D, Ke Z, Liu R, Maubach G, Zhuo L. Cathepsin S is aberrantly overexpressed in human hepatocellular carcinoma. Mol Med Rep. 2009;2:713–8. [DOI] [PubMed]

60.

Ruan J, Zheng H, Fu W, Zhao P, Su N, Luo R. Increased expression of cathepsin L: a novel independent prognostic marker of worse outcome in hepatocellular carcinoma patients. PLoS One. 2014;9:e112136. [DOI] [PubMed] [PMC]

61.

Zhang C, Liu Z, Wang X, Zhang B, Cui L, Hu Q, et al. Cathepsin K promotes the proliferation of hepatocellular carcinoma cells through induction of SIAH1 ubiquitination and degradation. iScience. 2023;26:106852. [DOI] [PubMed] [PMC]

62.

Huang X, Deng H, Zhang B, Wang K, Qu Y, Li T, et al. The causal relationship between cathepsins and digestive system tumors: a Mendelian randomization study. Front Oncol. 2024;14:1365138. [DOI] [PubMed] [PMC]

63.

Liu J, Zhang W, Wang Z, Wang Y, Li T, Wang Y, et al. Cathepsin V is correlated with the prognosis and tumor microenvironment in liver cancer. Mol Carcinog. 2024;63:400–16. [DOI] [PubMed]

64.

Wang J, Chen L, Li Y, Guan XY. Overexpression of cathepsin Z contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma. PLoS One. 2011;6:e24967. [DOI] [PubMed] [PMC]

65.

Du Z, Liu X, Wei X, Luo H, Li P, Shi M, et al. Quantitative proteomics identifies a plasma multi-protein model for detection of hepatocellular carcinoma. Sci Rep. 2020;10:15552. [DOI] [PubMed] [PMC]

66.

Xu ZZ, Xiu P, Lv JW, Wang FH, Dong XF, Liu F, et al. Integrin αvβ3 is required for cathepsin B-induced hepatocellular carcinoma progression. Mol Med Rep. 2015;11:3499–504. [DOI] [PubMed]

67.

Scharf JG, Braulke T, Hartmann H, Ramadori G. Regulation of the components of the 150 kDa IGF binding protein complex in cocultures of rat hepatocytes and Kupffer cells by 3’,5’-cyclic adenosine monophosphate. J Cell Physiol. 2001;186:425–36. [DOI] [PubMed]

68.

Conover CA, Perry JE, Tindall DJ. Endogenous cathepsin D-mediated hydrolysis of insulin-like growth factor-binding proteins in cultured human prostatic carcinoma cells. J Clin Endocrinol Metab. 1995;80:987–93. [DOI] [PubMed]

69.

Lei T, Ling X. IGF-1 promotes the growth and metastasis of hepatocellular carcinoma via the inhibition of proteasome-mediated cathepsin B degradation. World J Gastroenterol. 2015;21:10137–49. [DOI] [PubMed] [PMC]

70.

Fan Q, Wang X, Zhang H, Li C, Fan J, Xu J. Silencing cathepsin S gene expression inhibits growth, invasion and angiogenesis of human hepatocellular carcinoma in vitro. Biochem Biophys Res Commun. 2012;425:703–10. [DOI] [PubMed]

71.

Guicciardi ME, Bronk SF, Werneburg NW, Gores GJ. cFLIPL prevents TRAIL-induced apoptosis of hepatocellular carcinoma cells by inhibiting the lysosomal pathway of apoptosis. Am J Physiol Gastrointest Liver Physiol. 2007;292:G1337–46. [DOI] [PubMed]

72.

Ullio C, Casas J, Brunk UT, Sala G, Fabriàs G, Ghidoni R, et al. Sphingosine mediates TNFα-induced lysosomal membrane permeabilization and ensuing programmed cell death in hepatoma cells. J Lipid Res. 2012;53:1134–43. [DOI] [PubMed] [PMC]

73.

Desideri E, Ciriolo MR. Inhibition of JNK increases the sensitivity of hepatocellular carcinoma cells to lysosomotropic drugs via LAMP2A destabilization. Cell Death Discov. 2021;7:29. [DOI] [PubMed] [PMC]

74.

Droga-Mazovec G, Bojic L, Petelin A, Ivanova S, Romih R, Repnik U, et al. Cysteine cathepsins trigger caspase-dependent cell death through cleavage of bid and antiapoptotic Bcl-2 homologues. J Biol Chem. 2008;283:19140–50. [DOI] [PubMed]

75.

Heinrich M, Neumeyer J, Jakob M, Hallas C, Tchikov V, Winoto-Morbach S, et al. Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and -3 activation. Cell Death Differ. 2004;11:550–63. [DOI] [PubMed]

76.

Wang X, Xiong L, Yu G, Li D, Peng T, Luo D, et al. Cathepsin S silencing induces apoptosis of human hepatocellular carcinoma cells. Am J Transl Res. 2015;7:100–10. [PubMed] [PMC]

77.

Fei M, Zhang L, Wang H, Zhu Y, Niu W, Tang T, et al. Inhibition of Cathepsin S Induces Mitochondrial Apoptosis in Glioblastoma Cell Lines Through Mitochondrial Stress and Autophagosome Accumulation. Front Oncol. 2020;10:516746. [DOI] [PubMed] [PMC]

78.

Seo SU, Woo SM, Min KJ, Kwon TK. Z-FL-COCHO, a cathepsin S inhibitor, enhances oxaliplatin-induced apoptosis through upregulation of Bim expression. Biochem Biophys Res Commun. 2018;498:849–54. [DOI] [PubMed]

79.

Soond SM, Savvateeva LV, Makarov VA, Gorokhovets NV, Townsend PA, Zamyatnin AA Jr. Cathepsin S Cleaves BAX as a Novel and Therapeutically Important Regulatory Mechanism for Apoptosis. Pharmaceutics. 2021;13:339. [DOI] [PubMed] [PMC]

80.

Chen Q, Qu S, Liang Z, Liu Y, Chen H, Ma S, et al. Cathepsin H Knockdown Reverses Radioresistance of Hepatocellular Carcinoma via Metabolic Switch Followed by Apoptosis. Int J Mol Sci. 2023;24:5257. [DOI] [PubMed] [PMC]

81.

Wang SJ, Chao D, Wei W, Nan G, Li JY, Liu FL, et al. CD147 promotes collective invasion through cathepsin B in hepatocellular carcinoma. J Exp Clin Cancer Res. 2020;39:145. [DOI] [PubMed] [PMC]

82.

Chen WN, Chen JY, Jiao BY, Lin WS, Wu YL, Liu LL, et al. Interaction of the hepatitis B spliced protein with cathepsin B promotes hepatoma cell migration and invasion. J Virol. 2012;86:13533–41. [DOI] [PubMed] [PMC]

83.

Xu LB, Qin YF, Su L, Huang C, Xu Q, Zhang R, et al. Cathepsin-facilitated invasion of BMI1-high hepatocellular carcinoma cells drives bile duct tumor thrombi formation. Nat Commun. 2023;14:7033. [DOI] [PubMed] [PMC]

84.

Lyu L, Jin X, Li Z, Liu S, Li Y, Su R, et al. TBBPA regulates calcium-mediated lysosomal exocytosis and thereby promotes invasion and migration in hepatocellular carcinoma. Ecotoxicol Environ Saf. 2020;192:110255. [DOI] [PubMed]

85.

Zhang GP, Yue X, Li SQ. Cathepsin C Interacts with TNF-α/p38 MAPK Signaling Pathway to Promote Proliferation and Metastasis in Hepatocellular Carcinoma. Cancer Res Treat. 2020;52:10–23. [DOI] [PubMed] [PMC]

86.

Zhang Z, Zhang H, Peng T, Li D, Xu J. Melittin suppresses cathepsin S-induced invasion and angiogenesis via blocking of the VEGF-A/VEGFR-2/MEK1/ERK1/2 pathway in human hepatocellular carcinoma. Oncol Lett. 2016;11:610–8. [DOI] [PubMed] [PMC]

87.

Zhang C, Yang H, Pan L, Zhao G, Zhang R, Zhang T, et al. Hepatitis B Virus X Protein (HBx) Suppresses Transcription Factor EB (TFEB) Resulting in Stabilization of Integrin Beta 1 (ITGB1) in Hepatocellular Carcinoma Cells. Cancers (Basel). 2021;13:1181. [DOI] [PubMed] [PMC]

88.

Pan Y, Yu Y, Wang X, Zhang T. Tumor-Associated Macrophages in Tumor Immunity. Front Immunol. 2020;11:583084. [DOI] [PubMed] [PMC]

89.

Sharma A, Seow JJW, Dutertre CA, Pai R, Blériot C, Mishra A, et al. Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma. Cell. 2020;183:377–94.e21. [DOI] [PubMed]

90.

Fan G, Xie T, Li L, Tang L, Han X, Shi Y. Single-cell and spatial analyses revealed the co-location of cancer stem cells and SPP1+ macrophage in hypoxic region that determines the poor prognosis in hepatocellular carcinoma. NPJ Precis Oncol. 2024;8:75. [DOI] [PubMed] [PMC]

91.

Lu Y, Yang A, Quan C, Pan Y, Zhang H, Li Y, et al. A single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma. Nat Commun. 2022;13:4594. [DOI] [PubMed] [PMC]

92.

Gocheva V, Wang HW, Gadea BB, Shree T, Hunter KE, Garfall AL, et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev. 2010;24:241–55. [DOI] [PubMed] [PMC]

93.

Oelschlaegel D, Weiss Sadan T, Salpeter S, Krug S, Blum G, Schmitz W, et al. Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages. Cancers (Basel). 2020;12:2579. [DOI] [PubMed] [PMC]

94.

Lee SG, Woo SM, Seo SU, Lee CH, Baek MC, Jang SH, et al. Cathepsin D promotes polarization of tumor-associated macrophages and metastasis through TGFBI-CCL20 signaling. Exp Mol Med. 2024;56:383–94. [DOI] [PubMed] [PMC]

95.

Gondi CS, Rao JS. Cathepsin B as a cancer target. Expert Opin Ther Targets. 2013;17:281–91. [DOI] [PubMed] [PMC]

96.

Sudhan DR, Siemann DW. Cathepsin L targeting in cancer treatment. Pharmacol Ther. 2015;155:105–16. [DOI] [PubMed] [PMC]

97.

Katunuma N. Structure-based development of specific inhibitors for individual cathepsins and their medical applications. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87:29–39. [DOI] [PubMed] [PMC]

98.

Yu PW, Kao G, Dai Z, Nasertorabi F, Zhang Y. Rational design of humanized antibody inhibitors for cathepsin S. Arch Biochem Biophys. 2024;751:109849. [DOI] [PubMed]

99.

Duong LT, Wesolowski GA, Leung P, Oballa R, Pickarski M. Efficacy of a cathepsin K inhibitor in a preclinical model for prevention and treatment of breast cancer bone metastasis. Mol Cancer Ther. 2014;13:2898–909. [DOI] [PubMed]

100.

Biasizzo M, Javoršek U, Vidak E, Zarić M, Turk B. Cysteine cathepsins: A long and winding road towards clinics. Mol Aspects Med. 2022;88:101150. [DOI] [PubMed]