Advertisement

ResearchIn-Press PreviewImmunologyInflammationMetabolism Open Access | 10.1172/JCI198076

GSDME/IL-18 pyroptotic axis prevents myosteatosis by expanding tissue-resident macrophages to promote muscle regeneration

Qi Cao,1 Jian Liu,2 Gang Huang,3 Su-Yuan Wang,1 Guo-Dong Lu,1 Yong Huang,1 Yi-Ting Chen,1 Zhen Zhang,4 Jiang-Tao Fu,1 Si-Jia Sun,4 Xiaofei Chen,1 Chunlin Zhuang,1 Chunquan Sheng,1 Fu-Ming Shen,4 Dong-Jie Li,4 and Pei Wang1

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Cao, Q. in: PubMed | Google Scholar

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Liu, J. in: PubMed | Google Scholar

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Huang, G. in: PubMed | Google Scholar

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Wang, S. in: PubMed | Google Scholar

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Lu, G. in: PubMed | Google Scholar

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Huang, Y. in: PubMed | Google Scholar

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Chen, Y. in: PubMed | Google Scholar

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Zhang, Z. in: PubMed | Google Scholar

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Fu, J. in: PubMed | Google Scholar

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Sun, S. in: PubMed | Google Scholar

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Chen, X. in: PubMed | Google Scholar

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Zhuang, C. in: PubMed | Google Scholar

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Sheng, C. in: PubMed | Google Scholar

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Shen, F. in: PubMed | Google Scholar

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Li, D. in: PubMed | Google Scholar

1Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), Naval Medical University, Shanghai, China

2Department of Hepatic Surgery, Naval Medical University, Shanghai, China

3Department of Urology, Baoshan Renhe Hospital, Shanghai University, Shanghai, China, Shanghai, China

4Department of Pharmacy, Tongji University, Shanghai, China

Find articles by Wang, P. in: PubMed | Google Scholar |

Published February 17, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI198076.
Copyright © 2026, Cao et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 17, 2026 - Version history
View PDF
Abstract

Metabolic-inflammatory crosstalk orchestrates muscle repair. Although pyroptosis typically aggravates sterile injury, we demonstrated that GSDME-dependent pyroptotic signaling associated with recruited myeloid cells paradoxically supported regeneration. GSDME expression was induced in post-surgical human muscle injury and murine damage models. Gsdme deficiency delayed functional recovery and exacerbated injury-induced myosteatosis, a pathological form of intramuscular ectopic fat deposition. Time-series and single-cell RNA-sequencing analyses revealed that GSDME loss shifted the transcriptional program from oxidative metabolism toward lipid storage and adipogenesis. Lipidomics confirmed aberrant accumulation of triacylglycerols and sphingolipids in Gsdme-deficient muscle. Single-cell profiling further identified divergent fibro-adipogenic progenitors (FAPs) states skewed toward adipogenesis, accompanied by impaired expansion of restorative Lyve1⁺Cd163⁺Txnip⁺ tissue-resident macrophages (TRMs)—validated by multiplex flow cytometry. Blocking CCR2-dependent monocyte recruitment produced regenerative defects comparable to those caused by Gsdme deficiency. Myeloid-specific Gsdme reintroduction rescued TRM expansion and function, curbed FAP adipogenic reprogramming, whereas FAP-specific expression proved ineffective. Mechanistically, IL-18 downstream of GSDME-dependent signaling engaged KLF4/JUN signaling in TRMs, sustaining their reparative and lipid-clearing capacity. This GSDME–IL-18–TRMs axis was compromised in aged muscle, yet exogenous IL-18 reversed myosteatosis and accelerated regeneration. Together, these findings suggest that GSDME-dependent pyroptotic signaling can act as a metabolic checkpoint that sustains TRM-driven lipid homeostasis to support muscle regeneration.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View

View Supplemental Table 1

View Supplemental Table 2

Version history
  • Version 1 (February 17, 2026): In-Press Preview
Advertisement
Advertisement