Cannabidiol suppresses M2-like macrophage polarization via TRPV4/RhoA/ROCK signaling to alleviate hepatic fibrosis
- 1Clinical Laboratory Center, The Affiliated Hospital of Guizhou Medical University
- 2Department of Medical Examination, Guizhou Medical University
- 3Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital Bijie Hospital
Abstract
Background: Dysregulated buildup of extracellular matrix constitutes a hallmark of hepatic fibrosis, loss of liver architectural integrity, and impaired hepatic functional capacity. Pro-fibrogenic M2-polarized macrophages promote the transdifferentiation of hepatic stellate cells and facilitate fibrotic progression. Cannabidiol (CBD) exhibits immunomodulatory and anti-fibrotic properties. However, whether CBD regulates M2-like macrophage polarization to mitigate hepatic fibrogenesis remains unclear.
Objective: Cannabidiol-driven mitigation of pathological hepatic remodeling was evaluated, with its molecular regulatory mechanisms systematically clarified.
Methods: The modulation of liver fibrosis by cannabidiol was investigated in vitro and in vivo . A model was created using bile duct ligation (BDL). Anti-fibrotic effects were tested with liver function tests, histopathology, immunohistochemistry, and immunofluorescence. Co-culture systems comprising THP-1-derived macrophages and LX-2 stellate cells were constructed to delineate cannabidiol-mediated regulation of M2-like macrophage polarization and hepatic stellate cell transactivation. Transcriptomic, single-cell transcriptomic, network pharmacology, molecular docking simulation, and dynamic conformational approaches explored cannabidiol’s binding to TRPV4. Western blot, qRT-PCR, flow cytometry, CETSA, Co-IP, and mass spectrometry detected macrophage polarization and under-healing pathway markers. Transwell and colony-formation assays assessed the effects of conditioned medium from CBD-treated M2-like macrophages on LX-2 cell migration, proliferation, and activation.
Results: Cannabidiol mitigated hepatic damage, fibrogenic progression, and inflammatory responses in BDL-operated mice, supported by ameliorated hepatic functional indices and reduced fibrotic biomarkers. CBD inhibited IL-4-induced M2-like polarization in THP-1 cells, resulting in decreased expression of M2-associated markers and pro-fibrotic factors. Mechanistically, CBD may engage TRPV4 and suppress RhoA/ROCK signaling, while concurrently modulating STAT6 phosphorylation. These molecular actions inhibited LX-2 cell activation, as indicated by reduced Col-I and α-SMA expression, along with diminished migration and proliferation. CBD further reduced collagen deposition and M2-associated macrophage infiltration in hepatic tissue. Notably, co-administration of CBD with a TRPV4 inhibitor potentiated anti-fibrotic effects both in vivo and in vitro .
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BibTeX
@article{zhao2026cannabidiol,
title = {{Cannabidiol suppresses M2-like macrophage polarization via TRPV4/RhoA/ROCK signaling to alleviate hepatic fibrosis}},
author = {Peiling Zhao and Yongmei Liu and Lian Wang and Manqin Yuan and Xiaosu Wang and Ping He and Yuping Wang},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1951332},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1951332/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cannabidiol suppresses M2-like macrophage polarization via TRPV4/RhoA/ROCK signaling to alleviate hepatic fibrosis
AU - Peiling Zhao
AU - Yongmei Liu
AU - Lian Wang
AU - Manqin Yuan
AU - Xiaosu Wang
AU - Ping He
AU - Yuping Wang
PY - 2026
DA - 2026/10/20
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1951332
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1951332/full
AB - Background: Dysregulated buildup of extracellular matrix constitutes a hallmark of hepatic fibrosis, loss of liver architectural integrity, and impaired hepatic functional capacity. Pro-fibrogenic M2-polarized macrophages promote the transdifferentiation of hepatic stellate cells and facilitate fibrotic progression. Cannabidiol (CBD) exhibits immunomodulatory and anti-fibrotic properties. However, whether CBD regulates M2-like macrophage polarization to mitigate hepatic fibrogenesis remains unclear. Objective: Cannabidiol-driven mitigation of pathological hepatic remodeling was evaluated, with its molecular regulatory mechanisms systematically clarified. Methods: The modulation of liver fibrosis by cannabidiol was investigated in vitro and in vivo . A model was created using bile duct ligation (BDL). Anti-fibrotic effects were tested with liver function tests, histopathology, immunohistochemistry, and immunofluorescence. Co-culture systems comprising THP-1-derived macrophages and LX-2 stellate cells were constructed to delineate cannabidiol-mediated regulation of M2-like macrophage polarization and hepatic stellate cell transactivation. Transcriptomic, single-cell transcriptomic, network pharmacology, molecular docking simulation, and dynamic conformational approaches explored cannabidiol’s binding to TRPV4. Western blot, qRT-PCR, flow cytometry, CETSA, Co-IP, and mass spectrometry detected macrophage polarization and under-healing pathway markers. Transwell and colony-formation assays assessed the effects of conditioned medium from CBD-treated M2-like macrophages on LX-2 cell migration, proliferation, and activation. Results: Cannabidiol mitigated hepatic damage, fibrogenic progression, and inflammatory responses in BDL-operated mice, supported by ameliorated hepatic functional indices and reduced fibrotic biomarkers. CBD inhibited IL-4-induced M2-like polarization in THP-1 cells, resulting in decreased expression of M2-associated markers and pro-fibrotic factors. Mechanistically, CBD may engage TRPV4 and suppress RhoA/ROCK signaling, while concurrently modulating STAT6 phosphorylation. These molecular actions inhibited LX-2 cell activation, as indicated by reduced Col-I and α-SMA expression, along with diminished migration and proliferation. CBD further reduced collagen deposition and M2-associated macrophage infiltration in hepatic tissue. Notably, co-administration of CBD with a TRPV4 inhibitor potentiated anti-fibrotic effects both in vivo and in vitro .
SN - 1664-3224
ER -