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
  • 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: [email protected].
  • 3. School of Pharmacy, Anhui Medical University, Hefei 230032, China. Electronic address: [email protected].
  • 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: [email protected].
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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