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

Acta Pharmacologica Sinica volume 46, pages 1946–1957 (2025)Cite this article

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.

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Fig. 1: Hepatic FNDC5/Irisin is positively correlated with APAP-induced liver injury.
Fig. 2: Fndc5/Irisin deficiency protects against APAP-induced liver injury in mice.
Fig. 3: Exogenous Irisin intensifies APAP-induced AILI.
Fig. 4: Irisin mediated APAP-induced hepatocyte damage.
Fig. 5: Irisin triggers multiple inflammatory pathways in AILI.
Fig. 6: Irisin amplifies JNK and NF-κB activation to intensify the inflammatory response in APAP-induced liver injury.
Fig. 7: Irisin exacerbates APAP-induced hepatocyte inflammation and oxidative stress by relying on the integrin αV-JNK/NF-κB axis.

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Acknowledgements

This study was supported by the China Postdoctoral Science Foundation (2024M752443 to WWZ), Postdoctoral Fellowship Program of CPSF (GZC20231957 to WWZ). We thank Scientific Research Center of Wenzhou Medical University for consultation and instrument availability that supported this work.

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Author notes

  1. These authors contributed equally: Qian-hui Zhang, Lei-ming Jin.

Authors and Affiliations

  1. Department of Cardiology and Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China

    Qian-hui Zhang, Lei-ming Jin, Yong-qiang Xiong, Wu Luo, Wei-wei Zhu & Guang Liang

  2. Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji, 133002, China

    Qian-hui Zhang

  3. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China

    Qian-hui Zhang, Lei-ming Jin, Meng-sha Lin, Min-xiu Wang, Ya-qian Cui, Jia-xi Ye, Wu Luo, Wei-wei Zhu & Guang Liang

  4. The Affiliated Cangnan Hospital, Wenzhou Medical University, Wenzhou, 325800, China

    Wu Luo & Wei-wei Zhu

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Contributions

GL, WWZ, and WL designed the research and provided comprehensive supervision. QHZ, LMJ, and WWZ wrote the paper. QHZ, LMJ, MSL, MXW, and YQX performed research and were involved in data curation. QHZ, LMJ, YQC and JXY analyzed data. QHZ and LMJ contributed to the visualization.

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Correspondence to Wu Luo, Wei-wei Zhu or Guang Liang.

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Zhang, Qh., Jin, Lm., Lin, Ms. et al. FNDC5/Irisin exacerbates APAP-induced acute liver injury through activating JNK/NF-κB and inflammatory response. Acta Pharmacol Sin 46, 1946–1957 (2025). https://doi.org/10.1038/s41401-025-01509-7

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