2. Academic Validation
  3. A novel HDAC6 inhibitor attenuate APAP-induced liver injury by regulating MDH1-mediated oxidative stress

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

  • Int Immunopharmacol. 2024 Mar 13:131:111861. doi: 10.1016/j.intimp.2024.111861.
Guo-Dong Zhang 1,  Li-Li Wang 1,  Ling Zheng 1,  Shi-Qi Wang 1,  Rong-Quan Yang 1,  Yu-Ting He 1,  Jun-Wei Wang 1,  Ming-Yu Zhao 1,  Yi Ding 1,  Mei Liu 1,  Tian-Yu Yang 1,  Bao-Ming Wu 2,  Hao Cui 3,  Lei Zhang 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Anhui Medical University, Hefei 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei 230032, China.
  • 2 School of Pharmacy, Anhui Medical University, Hefei 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei 230032, China. Electronic address: wubaoming@ahmu.edu.cn.
  • 3 School of Pharmacy, Anhui Medical University, Hefei 230032, China. Electronic address: cuih1008@ahmu.edu.cn.
  • 4 School of Pharmacy, Anhui Medical University, Hefei 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei 230032, China. Electronic address: zhanglei-1@ahmu.edu.cn.
PMID: 38484665 DOI: 10.1016/j.intimp.2024.111861
Abstract

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.

Keywords

Acetylation; Histone deacetylase 6; Malate dehydrogenase 1; Oxidative stress.

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