2. Academic Validation
  3. Narirutin activates TFEB (transcription factor EB) to protect against acetaminophen-induced liver injury by targeting PPP3/calcineurin

Narirutin activates TFEB (transcription factor EB) to protect against acetaminophen-induced liver injury by targeting PPP3/calcineurin

  • Autophagy. 2023 Feb 13. doi: 10.1080/15548627.2023.2179781.
Zhiyuan Fang 1,  Yanyong Xu 2 3,  Guowen Liu 1,  Qi Shao 1,  Xiaodi Niu 4,  Wenjun Tai 1,  Taiyu Shen 1,  Minghe Fan 5,  Meng Chen 1,  Lin Lei 1,  Wenwen Gao 1,  Yuxiang Song 1,  Zhe Wang 1,  Xiliang Du 1,  Xinwei Li 1
Affiliations

Affiliations

  • 1 State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, 130062, Jilin, China.
  • 2 Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Pathology of School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 3 Frontier Innovation Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 4 College of Food Science and Engineering, Jilin University, Changchun, 130062, China.
  • 5 Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
PMID: 36779633 DOI: 10.1080/15548627.2023.2179781
Abstract

Acetaminophen (APAP) overdose is the predominant cause of drug-induced liver injury worldwide. The macroautophagy/autophagy-lysosomal pathway (ALP) is involved in the APAP hepatotoxicity. TFEB (transcription factor EB) promotes the expression of genes related to Autophagy and lysosomal biogenesis, thus, pharmacological activation of TFEB-mediated ALP may be an effective therapeutic approach for treating APAP-induced liver injury. We aimed to reveal the effects of narirutin (NR), the main bioactive constituents isolated from citrus peels, on APAP hepatotoxicity and to explore its underlying mechanism. Administration of NR enhanced activities of antioxidant enzymes, improved mitochondrial dysfunction and alleviated liver injury in APAP-treated mice, whereas NR did not affect APAP metabolism and MAPK/JNK activation. NR enhanced TFEB transcriptional activity and activated ALP in an mTOR complex 1 (mTORC1)-independent but PPP3/calcineurin-dependent manner. Moreover, knockout of Tfeb or knockdown of PPP3CB/CNA2 (protein Phosphatase 3, catalytic subunit, beta isoform) in the liver abolished the beneficial effects of NR on APAP overdose. Mechanistically, NR bound to PPP3CB via PRO31, LYS61 and PRO347 residues and enhanced PPP3/calcineurin activity, thereby eliciting dephosphorylation of TFEB and promoting ALP, which alleviated APAP-induced oxidative stress and liver injury. Together, NR protects against APAP-induced liver injury by activating a PPP3/calcineurin-TFEB-ALP axis, indicating NR may be a potential agent for treating APAP overdose.

Keywords

PPP3CB/CNA2; TFEB; autophagy-lysosomal pathway; hepatotoxicity; oxidative stress.

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