Fasudil inhibits the expression of C/EBP homologous protein to protect against liver injury in acetaminophen-overdosed mice

• Published in: Biochemical and biophysical research communications 2023-12, Vol.686, p.149166-149166, Article 149166
• Main Authors: Namba, Nanami, Kuwahara, Takehiro, Kondo, Yuki, Fukusaki, Kumiko, Miyata, Keishi, Oike, Yuichi, Irie, Tetsumi, Ishitsuka, Yoichi
• Format: Article
• Language: English
• Subjects: Acetaminophen - adverse effects; Animals; Chemical and Drug Induced Liver Injury - drug therapy; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - prevention & control; Chemical and Drug Induced Liver Injury, Chronic - metabolism; Liver - metabolism; Male; Mice; Mice, Inbred C57BL
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2023.149166

Acetaminophen (APAP) overdoses can cause severe liver injury. In this study, the protective effect of fasudil against APAP-induced liver injury was investigated. APAP (400 mg/kg) was administered to male C57BL/6J mice to induce liver injury, and fasudil (20 or 40 mg/kg) was injected 30 min before APAP administration. Fasudil markedly suppressed APAP-induced elevation in serum transaminase activity and hepatic necrosis and significantly reduced an increase in nitrotyrosine and DNA fragmentation. However, fasudil did not affect cytochrome P450 2E1 expression, N-acetyl-p-benzoquinone imine production or c-jun N-terminal kinase activation. In contrast, fasudil significantly inhibited an APAP-induced increase in expression of the transcription factor C/EBP homologous protein (CHOP) in the liver, accompanied by transcriptional suppression of ER stress-related molecules such as Ero1α, Atf4 and Grp78. These findings indicate that suppression of CHOP expression by fasudil exhibits a remarkable protective effect against APAP liver injury by regulating ER stress. We suggest that fasudil is a promising therapeutic candidate for treating APAP-induced liver injury.