2. Academic Validation
  3. Lactate derived from macrophages drives skin dermal fibroblasts phenotypic remodeling via MCT1-primed histone H3 lysine 23 lactylation in hypertrophic scar

Lactate derived from macrophages drives skin dermal fibroblasts phenotypic remodeling via MCT1-primed histone H3 lysine 23 lactylation in hypertrophic scar

  • Nat Commun. 2026 Feb 12;17(1):2694. doi: 10.1038/s41467-026-69388-y.
Yixuan Yuan # 1,  Yujie Xiao # 1,  Jie Zou # 2,  Liang Luo # 1,  Mengyang Li 1,  Kuo Shen 1 3,  Lai Wei 1,  Yihao Zhang 1,  Peng Wang 1,  Yan Chen 4,  Shixuan Zhuo 4,  Hao Zhang 1 5,  Shijie Song 1,  Yanhui Jia 1,  Kejia Wang 1,  Shiqing Jiang 1,  Hao Guan 6,  Dahai Hu 7
Affiliations

Affiliations

  • 1 Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  • 2 Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an, China.
  • 3 Department of Orthopedics, Air Force Hospital of Western Theater Command, Chengdu, China.
  • 4 Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 5 Department of Orthopedics, General Hospital of Western Theater Command, Chengdu, China.
  • 6 Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China. [email protected].
  • 7 Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China. [email protected].
  • # Contributed equally.
PMID: 41680147 DOI: 10.1038/s41467-026-69388-y
Abstract

Hypertrophic scar (HS) is a fibroproliferative disorder characterized by fibroblast hyperactivation and aberrant extracellular matrix deposition. This study identifies macrophage-derived lactate as a key mediator of fibroblast phenotypic remodeling via Monocarboxylate Transporter 1 (MCT1)-mediated histone H3 lysine 23 lactylation (H3K23la) in HS. Elevated lactate levels and MCT1 expression were observed in HS tissues, with macrophages in stiff mechanical microenvironments identified as the primary lactate source. Lactate influx through MCT1 upregulated H3K23la, thereby promoting transcriptional activation of profibrotic genes HEY2 and COL11A1. Mechanistically, HEY2 activated YAP1/SMAD2 signaling, while COL11A1 stabilized MCT1 to enhance lactate transport, forming a positive loop that amplified fibrosis. Fibroblast-specific MCT1 deletion or pharmacological inhibition of MCT1 in male mice reduced Collagen deposition, accelerated wound healing, and attenuated scar formation. Our findings redefine the macrophage-fibroblast crosstalk in HS and establish the MCT1-H3K23la-HEY2/COL11A1 axis, particularly its self-reinforcing loop, as a novel therapeutic target.

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