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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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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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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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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DOI: https://doi.org/10.1038/s41401-023-01171-x