Int J Biol Sci 2022; 18(5):2146-2162. doi:10.7150/ijbs.69116 This issue

Research Paper

Urolithin A protects against acetaminophen-induced liver injury in mice via sustained activation of Nrf2

Zhimin Gao1*, Wei Yi1*, Junyuan Tang1*, Yuling Sun1, Jianrong Huang1, Tian Lan2, Xiaoyan Dai1, Suowen Xu3, Zheng-Gen Jin4, Xiaoqian Wu1✉

1. Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences& The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou511436, China
2. Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
3. Department of Endocrinology and Metabolism, The First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei 230037, China
4. Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
*These authors contributed equally.

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Citation:
Gao Z, Yi W, Tang J, Sun Y, Huang J, Lan T, Dai X, Xu S, Jin ZG, Wu X. Urolithin A protects against acetaminophen-induced liver injury in mice via sustained activation of Nrf2. Int J Biol Sci 2022; 18(5):2146-2162. doi:10.7150/ijbs.69116. Available from https://www.ijbs.com/v18p2146.htm

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Abstract

Graphic abstract

Acetaminophen overdose is a leading cause of acute live failure worldwide. N-acetylcysteine (NAC), as the only antidote, is limited due to its narrow therapeutic time window. Here we demonstrated that Urolithin A (UA), a metabolite of ellagitannin natural products in the gastrointestinal flora, protected against acetaminophen-induced liver injury (AILI) and is superior to NAC in terms of dosage and therapeutical time window. Transcriptomics assay revealed that UA promotes mitophagy and activated Nrf2/ARE signaling in the liver. Consistent with that, mitophagy and Nrf2/ARE signaling were activated, with less oxidative stress in UA-treated liver. Subsequently, molecular docking and dynamics simulation study revealed a binding mode between UA and Nrf-2/Keap1 including the hydrogen-bonding network among oxygen atoms in UA with the Nrf-2/Keap1 residues Arg 415, Ser 508 and Ser 602, which in turn trigger Nrf2 nuclear translocation, subsequently leading to activation of Nrf-2 target genes (HO-1, NQO1). Of note, mitophagy inhibition failed to prevent the protection of UA against AILI, which instead was compromised with Nrf2 gene silencing both in vivo and in vitro. Collectively, our data indicate that UA alleviated acetaminophen-induced oxidative stress and hepatic necrosis via activating Nrf2/ARE signaling pathway, highlighting a therapeutical potential of UA for AILI.

Keywords: Acute liver injury, Acetaminophen, Mitophagy, Nrf2, Urolithin A