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Cited by 4Ion Channels and ReceptorsCalcium signaling and nucleotide metabolismPhagocytosis and Immune Regulation

Reactive Oxygen Species‐Mediated TRPM2 Activation Facilitates Phagocytosis of Macrophages to Reverse Profibrotic Phenotype

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Zhang, Shaoying, Liang, Fanfan, Wan, Dan, Zhang, Chongyu, Zhang, Yinggang, Zhang, Xurui, Huang, Na, Feng, Keping +10 more·2025·Liver International
DOI 10.1111/liv.70341PMC PMC12435147
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Abstract

Background and Aims: Macrophages play plastic roles during fibrogenesis and fibrosis regression. Phagocytosis is considered a trigger for shifting macrophages from a profibrotic phenotype to a restorative phenotype. However, the underlying mechanism by which macrophages enhance phagocytosis remains unclear. Our present study investigated the role of reactive oxygen species (ROS)‐modulated TRPM2 activation in this process. Methods: The changes of TRPM2 expression, ROS intensity, and macrophage phagocytosis were assessed in fibrogenesis and fibrosis regression models. RNA sequencing was utilised to reveal pathway enrichment caused by TRPM2, and the role of TRPM2 in enhancing phagocytosis was verified. The coordinate regulation of ROS‐TRPM2 in different functions of macrophages was demonstrated by modulating ROS intensity and TRPM2 expression. Mitochondrial dynamics changes induced by ROS‐stimulated TRPM2 activation were evaluated by analysing the expression of dynamics‐related molecules and mitochondrial imaging, and intervention in mitochondrial dynamics confirmed their impact on macrophage phagocytosis. Results: Low‐intensity ROS stimulation up‐regulated the expression of TRPM2 and coordinately enhanced macrophage phagocytosis and the expression of matrix degradation‐related proteins (MMPs), a process akin to fibrosis regression. However, high‐intensity ROS inclined macrophages to produce more profibrotic cytokines, associating with oxidative stress caused by liver injury. ROS‐mediated TRPM2 activation mobilised Ca 2+ and promoted mitochondrial fission; either inhibiting mitochondrial fission or chelating Ca 2+ counteracted phagocytosis, as well as decreasing MMPs. Conclusions: ROS‐TRPM2 coordinately regulate macrophage functions. During the liver fibrosis regression period, ROS‐induced activation of TRPM2 helps enhance macrophage phagocytosis and switches them to a restorative phenotype. Modulating this process may provide means for developing effective therapeutic strategies.

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  • In a CCl4-induced mouse model, low levels of reactive oxygen species generated during fibrosis regression induce expression of TRPM2 channels in macrophages.

    “Using a CCl4-induced mouse model, Zhang et al. (6) demonstrated that low levels of reactive oxygen species (ROS) generated during fibrosis regression induce expression of the transient receptor potential melastatin 2 (TRPM2) channels in macrophages.”

    From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [6]

  • TRPM2 activation involves increased calcium-dependent mitochondrial fission in TRPM2+ macrophages, which augments efferocytosis and facilitates the transition from a pro-fibrotic to a pro-resolutive state.

    “Mechanistically, this process involves increased calcium-dependent mitochondrial fission in TRPM2+ macrophages, which augments efferocytosis and facilitates the transition from a pro-fibrotic to a pro-resolutive state.”

    From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [6]

  • Activation of TRPM2 promotes acquisition of a restorative phenotype and enhances macrophage phagocytic activity.

    “Activation of TRPM2 promotes acquisition of a restorative phenotype and enhances macrophage phagocytic activity.”

    From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [6]

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Cited by

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Authors
Zhang, S., Liang, F., Wan, D., Zhang, C., Zhang, Y., Zhang, X., Huang, N., Feng, K., Liang, X., Guo, N., Zhang, C., Zhou, Z., Li, Y., Geng, J., Liu, P., Kong, G., Lu, S., & Li, Z.
Affiliations
Second Affiliated Hospital of Xi'an Jiaotong University (CN)
Corresponding author
Li, Zongfang
ORCID
Venue
Liver International
Publisher
Wiley
Published
2025-09-15
Volume
45
Issue
10
Pages
e70341-e70341
ISSN
  • 0106-9543 (ISSN-L)
  • 1478-3223
  • 1478-3231
DOI
10.1111/liv.70341
PMC
PMC12435147
OpenAlex
W4414167267
Cited by
4
References
5
Citations by year
2026: 4
FWCI
2.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Liver International (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
Funders
  • National Natural Science Foundation of China (82101915, 82471849, 91842307)
  • Natural Science Foundation of Shaanxi Province (2023‐JC‐QN‐0918, 2023‐JC‐YB‐647)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
TRPM2, reactive oxygen species, macrophage phagocytosis, liver fibrosis regression, fibrogenesis, macrophage phenotype switching, mitochondrial fission, calcium signaling, matrix metalloproteinases, oxidative stress, liver injury
MeSH terms
Animals, Fibrosis, Humans, Macrophages, Male, Mice, Inbred C57BL, Phagocytosis, Phenotype, Reactive Oxygen Species, TRPM Cation Channels, Mice, Mitochondrial Dynamics

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