Carfilzomib shows therapeutic potential for reduction of liver fibrosis by targeting hepatic stellate cell activation.

Autor: Fujiwara A; Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.; Laboratory of Pharmacology and Pharmacotherapeutics, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, 525-8577, Japan., Takemura K; Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.; Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan., Tanaka A; Laboratory of Pharmacology and Pharmacotherapeutics, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, 525-8577, Japan., Matsumoto M; Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.; Department of Clinical Pharmacology and Pharmacotherapy, Wakayama Medical University, Wakayama, Japan., Katsuyama M; Radioisotope Center, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan., Okanoue T; Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka, Japan., Yamaguchi K; Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan., Itoh Y; Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan., Iwata K; Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan., Amagase K; Laboratory of Pharmacology and Pharmacotherapeutics, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, 525-8577, Japan., Umemura A; Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. aumemura@koto.kpu-m.ac.jp.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Aug 20; Vol. 14 (1), pp. 19288. Date of Electronic Publication: 2024 Aug 20.
DOI: 10.1038/s41598-024-70296-8
Abstrakt: Because hepatic stellate cells (HSCs) play a major role in fibrosis, we focused on HSCs as a potential target for the treatment of liver fibrosis. In this study, we attempted to identify drug candidates to inactivate HSCs and found that several proteasome inhibitors (PIs) reduced HSC viability. Our data showed that a second-generation PI, carfilzomib (CZM), suppressed the expression of fibrotic markers in primary murine HSCs at low concentrations of 5 or 10 nM. Since CZM was not toxic to HSCs up to a concentration of 12.5 nM, we examined its antifibrotic effects further. CZM achieved a clear reduction in liver fibrosis in the carbon tetrachloride (CCl 4 )-induced mouse model of liver fibrosis without worsening of liver injury. Mechanistically, RNA sequence analysis of primary HSCs revealed that CZM inhibits mitosis in HSCs. In the CCl 4 -injured liver, amphiregulin, which is known to activate mitogenic signaling pathways and fibrogenic activity and is upregulated in murine and human metabolic dysfunction-associated steatohepatitis (MASH), was downregulated by CZM administration, leading to inhibition of mitosis in HSCs. Thus, CZM and next-generation PIs in development could be potential therapeutic agents for the treatment of liver fibrosis via inactivation of HSCs without liver injury.
(© 2024. The Author(s).)
Databáze: MEDLINE
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