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Hesperetin derivative 2a inhibits lipopolysaccharide-induced acute liver injury in mice via downregulation of circDcbld2

Acta Pharmacologica Sinica volume 45, pages 354–365 (2024)Cite this article

Abstract

Acute liver injury (ALI) is a complex, life-threatening inflammatory liver disease, and persistent liver damage leads to rapid decline and even failure of liver function. However, the pathogenesis of ALI is still not fully understood, and no effective treatment has been discovered. Recent evidence shows that many circular RNAs (circRNAs) are associated with the occurrence of liver diseases. In this study we investigated the mechanisms of occurrence and development of ALI in lipopolysaccharide (LPS)-induced ALI mice. We found that expression of the circular RNA circDcbld2 was significantly elevated in the liver tissues of ALI mice and LPS-treated RAW264.7 cells. Knockdown of circDcbld2 markedly alleviates LPS-induced inflammatory responses in ALI mice and RAW264.7 cells. We designed and synthesized a series of hesperidin derivatives for circDcbld2, and found that hesperetin derivative 2a (HD-2a) at the concentrations of 2, 4, 8 μM effectively inhibited circDcbld2 expression in RAW264.7 cells. Administration of HD-2a (50, 100, 200 mg/kg. i.g., once 24 h in advance) effectively relieved LPS-induced liver dysfunction and inflammatory responses. RNA sequencing analysis revealed that the anti-inflammatory and hepatoprotective effects of HD-2a were mediated through downregulating circDcbld2 and suppressing the JAK2/STAT3 pathway. We conclude that HD-2a downregulates circDcbld2 to inhibit the JAK2/STAT3 pathway, thereby inhibiting the inflammatory responses in ALI. The results suggest that circDcbld2 may be a potential target for the prevention and treatment of ALI, and HD-2a may have potential as a drug for the treatment of ALI.

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Fig. 1: The abnormal expression of circDcbld2 is associated with the development of ALI in mice.
Fig. 2: Inhibition and overexpression of circDcbld2 regulated LPS-induced inflammatory responses in RAW264.7 cell.
Fig. 3: HD-2a inhibited circDcbld2 expression to alleviate liver injury in ALI mice.
Fig. 4: Anti-inflammatory effects of HD-2a on mice with acute liver injury.
Fig. 5: HD-2a attenuates inflammatory responses in LPS-treated RAW264.7 cells.
Fig. 6: HD-2a inhibited circDcbld2 to suppress JAK2/STAT3 signaling.
Fig. 7

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Nos. U19A2001, 82070628, 82300722), and funds from the University Synergy Innovation Programme of Anhui Province (GXXT-2020-063 and GXXT-2020-025), and the China Postdoctoral Science Foundation (2022M710178).

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Author notes

  1. These authors contributed equally: Li-jiao Sun, Xin Chen, Sai Zhu, Jin-jin Xu.

Authors and Affiliations

  1. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China

    Li-jiao Sun, Xin Chen, Sai Zhu, Jin-jin Xu, Xiao-feng Li, Shao-xi Diao, Ying-li Yang, Jin-yu Liu, Jia-nan Wang, Ying-yin Sun, Cheng Huang, Xiao-ming Meng, Hua Wang, Xiong-wen Lv & Jun Li

  2. The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China

    Li-jiao Sun, Xin Chen, Jin-jin Xu, Xiao-feng Li, Shao-xi Diao, Ying-li Yang, Jin-yu Liu, Jia-nan Wang, Cheng Huang, Xiao-ming Meng, Hua Wang, Xiong-wen Lv & Jun Li

  3. Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China

    Li-jiao Sun, Xin Chen, Jin-jin Xu, Shao-xi Diao, Ying-li Yang, Jin-yu Liu, Cheng Huang, Hua Wang, Xiong-wen Lv & Jun Li

  4. Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China

    Sai Zhu

  5. Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China

    Ying-yin Sun

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Contributions

LJS, XC, SZ designed the manuscript and performed the experiments; JJX, XFL, SXD analyzed the data; YLY, JYL contributed all samples, reagents and materials; JL contributed to all aspects of this study, data interpretation, and revised the manuscript for publication. All authors have revised and approved the final manuscript.

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Correspondence to Xiong-wen Lv or Jun Li.

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Sun, Lj., Chen, X., Zhu, S. et al. Hesperetin derivative 2a inhibits lipopolysaccharide-induced acute liver injury in mice via downregulation of circDcbld2. Acta Pharmacol Sin 45, 354–365 (2024). https://doi.org/10.1038/s41401-023-01171-x

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