Narirutin ameliorates alcohol-induced liver injury by targeting MAPK14 in zebrafish larvae

Ki-Hoon Park; Haytham Mohamedelfatih Mohamed Makki; Seok-Hyung Kim; Hyung-Joo Chung; Junyang Jung

doi:10.1016/j.biopha.2023.115350

Narirutin ameliorates alcohol-induced liver injury by targeting MAPK14 in zebrafish larvae

Biomed Pharmacother. 2023 Oct:166:115350. doi: 10.1016/j.biopha.2023.115350. Epub 2023 Aug 24.

Authors

Ki-Hoon Park¹, Haytham Mohamedelfatih Mohamed Makki², Seok-Hyung Kim³, Hyung-Joo Chung⁴, Junyang Jung⁵

Affiliations

¹ Department of Anesthesiology and Pain Medicine, College of Medicine, Kosin University, Seo-gu, Busan 49267, South Korea; Department of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, Dongdaemun-gu, Seoul 02447, South Korea.
² Department of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, Dongdaemun-gu, Seoul 02447, South Korea; Department of Biomedical Science, Graduation School, Kyung Hee University, Dongdaemun-gu, Seoul 02447, South Korea.
³ Sarcopenia Total Solution Center, Wonkwang University, Iksan 54538, South Korea. Electronic address: seokhyung1@wku.ac.kr.
⁴ Department of Anesthesiology and Pain Medicine, College of Medicine, Kosin University, Seo-gu, Busan 49267, South Korea. Electronic address: dmadjejs@kosin.ac.kr.
⁵ Department of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, Dongdaemun-gu, Seoul 02447, South Korea; Department of Biomedical Science, Graduation School, Kyung Hee University, Dongdaemun-gu, Seoul 02447, South Korea; Department of Precision Medicine, College of Medicine, Kyung Hee University, Dongdaemun-gu, Seoul 02447, South Korea. Electronic address: jjung@khu.ac.kr.

PMID: 37633055
DOI: 10.1016/j.biopha.2023.115350

Abstract

Background: Alcohol-associated liver disease (ALD) encompasses a range of hepatic abnormalities, including isolated alcoholic steatosis, steatohepatitis, and cirrhosis. The flavanone-7-O-glycoside narirutin (NRT), the primary flavonoid in citrus peel, has antioxidant, anti-inflammatory, and lipid-lowering activity. We investigated the effects of NRT on liver injury induced by alcohol and explored the underlying mechanisms.

Methods: Zebrafish larvae were used to investigate the effects of NRT on acute exposure to ethanol (EtOH). Liver phenotypic, morphological, and biochemical assessments were performed to evaluate the hepatoprotective effects of NRT. Network pharmacology and molecular docking analyses were conducted to identify candidate targets of NRT in EtOH-induced liver injury. A drug affinity responsive target stability (DARTS) assay was conducted to evaluate the binding of NRT to mitogen-activated protein kinase 14 (MAPK14). The mechanism of action of NRT was validated by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot analysis.

Results: The liver phenotypic, morphological, and biochemical assessments revealed that NRT has potential therapeutic effects against acute EtOH-induced liver injury. RT-qPCR confirmed that NRT reversed the change in the expression of genes related to oxidative stress, lipogenesis, and the endoplasmic reticulum (ER)/unfolded protein response pathway. Network pharmacology and molecular docking analyses identified potential targets of NRT's protective effects and confirmed that NRT regulates the p38 MAPK signaling pathway by targeting mitogen-activated protein kinase 14 (MAPK14).

Conclusions: NRT mitigates alcohol-induced liver injury by preventing lipid formation, protecting the antioxidant system, and suppressing ER stress-induced apoptosis through MAPK14 modulation.

Keywords: Alcohol-associated liver disease; Endoplasmic reticulum stress; Lipid metabolism; Narirutin; Network pharmacology; Zebrafish.

MeSH terms

Animals
Antioxidants / pharmacology
Chemical and Drug Induced Liver Injury, Chronic*
Ethanol / toxicity
Fatty Liver*
Flavanones*
Lipids
Liver Diseases, Alcoholic* / drug therapy
Liver Diseases, Alcoholic* / prevention & control
Mitogen-Activated Protein Kinase 14*
Molecular Docking Simulation
Zebrafish

Substances

Mitogen-Activated Protein Kinase 14
narirutin
Antioxidants
Ethanol
Flavanones
Lipids