A novel HDAC6 inhibitor attenuate APAP-induced liver injury by regulating MDH1-mediated oxidative stress

• DOI: 10.1016/j.intimp.2024.111861
• Publication Date: 2024-03-13T20:04:05Z
• Authors: Guo-dong Zhang; Li-li Wang; Ling Zheng; Shi-qi Wang; Rong-quan Yang; Yu-ting He; Jun-wei Wang; Ming-yu Zhao; Yi Ding; Mei Liu; Tian-yu Yang; Bao-ming Wu; Hao Cui; Lei Zhang
• Keywords: HDAC6; Acetaminophen

Glutathione (GSH) depletion, mitochondrial damage, and oxidative stress have been implicated in the pathogenesis of acetaminophen (APAP) hepatotoxicity. Here, we demonstrated that the expression of histone deacetylase 6 (HDAC6) is highly elevated, whereas malate dehydrogenase 1 (MDH1) is downregulated in liver tissues and AML-12 cells induced by APAP. The therapeutic benefits of LT-630, a novel HDAC6 inhibitor on APAP-induced liver injury, were also substantiated. On this basis, we demonstrated that LT-630 improved the protein expression and acetylation level of MDH1. Furthermore, after overexpression of MDH1, an upregulated NADPH/NADP+ ratio and GSH level and decreased cell apoptosis were observed in APAP-stimulated AML-12 cells. Importantly, MDH1 siRNA clearly reversed the protection of LT-630 on APAP-stimulated AML-12 cells. In conclusion, LT-630 could ameliorate liver injury by modulating MDH1-mediated oxidative stress induced by APAP.