2. Academic Validation
  3. FNDC5/Irisin exacerbates APAP-induced acute liver injury through activating JNK/NF-κB and inflammatory response

FNDC5/Irisin exacerbates APAP-induced acute liver injury through activating JNK/NF-κB and inflammatory response

  • Acta Pharmacol Sin. 2025 Feb 27. doi: 10.1038/s41401-025-01509-7.
Qian-Hui Zhang # 1 2 3,  Lei-Ming Jin # 1 3,  Meng-Sha Lin 3,  Min-Xiu Wang 3,  Ya-Qian Cui 3,  Jia-Xi Ye 3,  Yong-Qiang Xiong 1,  Wu Luo 4 5 6,  Wei-Wei Zhu 7 8 9,  Guang Liang 10 11
Affiliations

Affiliations

  • 1 Department of Cardiology and Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
  • 2 Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji, 133002, China.
  • 3 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
  • 4 Department of Cardiology and Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. wuluo@wmu.edu.cn.
  • 5 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. wuluo@wmu.edu.cn.
  • 6 The Affiliated Cangnan Hospital, Wenzhou Medical University, Wenzhou, 325800, China. wuluo@wmu.edu.cn.
  • 7 Department of Cardiology and Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. weiweizhu@wmu.edu.cn.
  • 8 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. weiweizhu@wmu.edu.cn.
  • 9 The Affiliated Cangnan Hospital, Wenzhou Medical University, Wenzhou, 325800, China. weiweizhu@wmu.edu.cn.
  • 10 Department of Cardiology and Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China. wzmcliangguang@163.com.
  • 11 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China. wzmcliangguang@163.com.
  • # Contributed equally.
PMID: 40016523 DOI: 10.1038/s41401-025-01509-7
Abstract

Acute liver injury (ALI) is associated with high mortality rates. Despite its severity, there are currently no effective interventions, underscoring the urgent need for research on the mechanisms driving ALI progression. Irisin, a hormone derived from its precursor FNDC5, has been shown to play a critical role in some chronic liver diseases. In this study we investigated the role of hepatic FNDC5/Irisin in a mouse model of AILI induced by acetaminophen (APAP, 400 mg/kg, i.p.). The mice were euthanized at 6, 12 and 24 h after APAP injection, then the blood and liver tissues were collected for analyses. By conducting transcriptome Sequencing, we identified that both the expression and release of FNDC5/Irisin were significantly increased and highly correlated with AILI. We showed that knockout of Irisin significantly improved APAP-induced tissue damage and hepatocyte death in mouse liver. Conversely, preinjection of recombinant Irisin protein (1 mg·kg-1·d-1, i.p., for 3 days) exacerbated the AILI in FNDC5 knockout mice. RNA-seq analysis revealed that knockout of FNDC5/Irisin reduced inflammatory responses and JNK/NF-κB activation in APAP-treated mouse liver, while exogenous Irisin administration aggravated JNK/NF-κB-mediated inflammation. In primary mouse hepatocytes treated with APAP (15 mM), application of Irisin (100 ng/mL) activated the Integrin αV/JNK/NF-κB axis, driving inflammation and oxidative stress. In summary, this study highlights Irisin as a critical regulator in AILI progression. Circulating Irisin could be a novel biomarker for AILI diagnosis, and targeting FNDC5/Irisin could hold promise for the development of novel treatments for AILI.

Keywords

FNDC5/Irisin; JNK/NF-κB; acetaminophen; acute liver injury; inflammation; oxidative stress.

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