Abstract
Liver fibrosis is a wound healing process in response to various chronic liver injuries characterized by the replacement of normal liver by collagen fibers formed from extracellular matrix (ECM), resulting in scarring of the organ. Liver macrophages, a highly heterogeneous and plastic immune cell population, are pivotal in human health and disease, widely involved in the advancement and reversal of liver fibrosis. Interleukin-4 (IL-4) and/or interleukin-13 (IL-13)-induced pro-fibrotic macrophage polarization play a crucial role in promoting liver fibrosis through the secretion of transforming growth factor-β (TGF-β), a key profibrotic cytokine. This study aimed to explore the therapeutic potential and underlying mechanism of pomolic acid (PA) in mitigating carbon tetrachloride (CCl4)-induced liver fibrosis. The results indicated that PA effectively hindered pro-fibrotic macrophage polarization and the release of TGF-β, thereby ameliorating the fibrotic progression. Mechanistically, PA disrupted β-arrestin 2-IRG1 interaction, consequently impeding the ubiquitination-related degradation of IRG1, and ultimately suppressed fatty acid oxidation (FAO)-mediated pro-fibrotic macrophage polarization. Furthermore, PA also demonstrated excellent efficacy in combating oral submucosal fibrosis (OSF). In conclusion, our study confirmed that PA inhibited the advancement of fibrosis by repressing β-arrestin 2-induced pro-fibrotic macrophage polarization. These findings suggest that PA could serve as a promising and broad-spectrum anti-fibrotic drug.
Data availability
Data will be made available on request.
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Funding
This research was funded by the National Natural Science Foundation of China (No. 82174271), the Natural Science Foundation of Hunan Province (No.2026JJ81069), and Hunan Provincial College Students’ Innovation and Entrepreneurship Training Program (S202410541093).
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XZ, GP, and JT designed the experiments; XZ performed the majority of the experiments; YZ carried out the immunofluorescence experiment; MR conducted the CETSA and DARTS experiments; XY performed all statistical analysis; XZ, YZ, GP, and JT wrote the manuscript. All the authors read and approved the final manuscript.
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The Institutional Ethical Committee on Animal Care and Experimentation of Hunan University of Chinese Medicine (HNUCMZI-2407-15) authorized the present research in accordance with the tenets of The Declaration of Helsinki. This study was conducted in accordance with ARRIVE guidelines.
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Zhu, X., Zhou, Y., Ruan, M. et al. Pomolic acid alleviates CCl4‑induced liver fibrosis in mice by suppressing β-arrestin 2-mediated pro-fibrotic macrophage polarization. Sci Rep (2026). https://doi.org/10.1038/s41598-026-45925-z
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DOI: https://doi.org/10.1038/s41598-026-45925-z
