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Gasdermin D-mediated metabolic crosstalk promotes tissue repair
Abstract
The establishment of an early pro-regenerative niche is crucial for tissue regeneration 1,2. Gasdermin D (GSDMD)-dependent pyroptosis accounts for the release of inflammatory cytokines upon various insults 3-5. However, little is known about its role in tissue regeneration followed by homeostatic maintenance. Here we show that macrophage GSDMD deficiency delays tissue recovery but has little effect on the local inflammatory milieu or the lytic pyroptosis process. Profiling of the metabolite secretome of hyperactivated macrophages revealed a non-canonical metabolite-secreting function of GSDMD. We further identified 11,12-epoxyeicosatrienoic acid (11,12-EET) as a bioactive, pro-healing oxylipin that is secreted from hyperactive macrophages in a GSDMD-dependent manner. Accumulation of 11,12-EET by direct supplementation or deletion of Ephx2, which encodes a 11,12-EET-hydrolytic enzyme, accelerated muscle regeneration. We further demonstrated that EPHX2 accumulated within aged muscle, and that consecutive 11,12-EET treatment rejuvenated aged muscle. Mechanistically, 11,12-EET amplifies fibroblast growth factor signalling by modulating liquid-liquid phase separation of fibroblast growth factors, thereby boosting the activation and proliferation of muscle stem cells. These data depict a GSDMD-guided metabolite crosstalk between macrophages and muscle stem cells that governs the repair process, which offers insights with therapeutic implications for the regeneration of injured or aged tissues.
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“However, whether all these pro-inflammatory subsets are entirely detrimental remains unclear, as some evidence suggests that a controlled inflammatory response may be necessary to initiate repair (42, 43).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [43]
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Metadata
- Authors
- Chi, Z., Chen, S., Yang, D., Cui, W., Lu, Y., Wang, Z., Li, M., Yu, W., Zhang, J., Jiang, Y., Sun, R., Yu, Q., Hu, T., Lu, X., Deng, Q., Yang, Y., Zhao, T., Chang, M., Li, Y., Zhang, X., Shang, M., Xiao, Q., Ding, K., & Wang, D.
- Affiliations
- Sir Run Run Shaw Hospital (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Zhejiang University (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Chi, Zhexu
- Wang, Di
- ORCID
- Venue
- Nature
- Published
- 2024-09-11
- Volume
- 634
- Issue
- 8036
- Pages
- 1168-1177
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W4402438036
- Cited by
- 116
- References
- 57
- Citations by year
- 2026: 54 · 2025: 57 · 2024: 5
- FWCI
- 18.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- gasdermin D, pyroptosis, macrophages, 11,12-epoxyeicosatrienoic acid, oxylipins, EPHX2, muscle regeneration, muscle aging, FGF signaling, liquid-liquid phase separation, muscle stem cells, tissue repair, metabolite secretion
- MeSH terms
- Pyroptosis, Gasdermins, Aging, Animals, Epoxide Hydrolases, Female, Homeostasis, Humans, Macrophages, Male, Mice, Inbred C57BL, Regeneration, Rejuvenation, Wound Healing, 8,11,14-Eicosatrienoic Acid, Muscle, Skeletal, Phosphate-Binding Proteins, Intracellular Signaling Peptides and Proteins, Mice, Oxylipins
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