Table Info

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]	-	-

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

Not applicable.

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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