Targeting the lactate/P300/H3K18la epigenetic pathway with a mechanoadaptive biomimetic hydrogel to suppress traumatic tendon heterotopic ossification.
9 affiliations
- 1Department of Pediatric Orthopedic, Center for Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong Province, 510515, China.
- 2Department of Sports Medicine, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong Province, 510515, China.
- 3The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, 510515, China.
- 4Division of Orthopaedic Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
- 5Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Sun Yat-Sen University, Guangzhou, Guangdong, 510000, China.
- 6Southern Medical University, Guangzhou, Guangdong Province, 510515, China.
- 7First Department of Neurology, First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, 650031, China.
- 8Department of Pathology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian Province, 361004, China.
- 9Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China.
Abstract
Traumatic heterotopic ossification (HO) is a debilitating complication of tendon injury, yet its pathogenic mechanisms remain elusive and effective preventive strategies are lacking. Here, we identify a glycometabolic-epigenetic axis that drives HO progression. Single-cell profiling and functional analyses reveal that hypoxic chondrocytes undergo glycolytic reprogramming, leading to lactate accumulation and transfer into tendon-derived mesenchymal stem cells (TD-MSCs) through MCT1. This metabolic coupling promotes P300-dependent histone H3 lysine 18 lactylation (H3K18la), activating osteogenic programs characterized by Col6a1, Zhx3, Lox and Vdr expression and thereby facilitating pathological endochondral ossification. Guided by this mechanism, we develop a tendon-adhesive hydrogel (GelHA-A485@Exos) that integrates mechanical repair with targeted epigenetic modulation. MSC-derived exosomes enable localized delivery of the P300 inhibitor A485, suppressing H3K18la and aberrant osteogenic activation, while the hydrogel scaffold enhances tendon regeneration. In vivo and in vitro studies demonstrate that GelHA-A485@Exos promotes tendon healing while preventing HO formation. Our findings establish metabolic-epigenetic communication as a central regulator of traumatic HO and provide a translational therapeutic strategy for its clinical prevention.
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BibTeX
@article{feng2026targeting,
title = {{Targeting the lactate/P300/H3K18la epigenetic pathway with a mechanoadaptive biomimetic hydrogel to suppress traumatic tendon heterotopic ossification.}},
author = {Haoyang Feng and Kai Ang and Zengfa Deng and Chonghe Cui and Jialan Chen and Nanfeng Huang and Yimei Feng and Jimei Zhang and Danlin Li and Zhen Kong and Zicheng Cai and Yongjian Sun and Yusheng Yang},
journal = {Bioactive materials},
year = {2026},
month = oct,
doi = {10.1016/j.bioactmat.2026.10.006},
url = {https://europepmc.org/article/MED/42927122},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Targeting the lactate/P300/H3K18la epigenetic pathway with a mechanoadaptive biomimetic hydrogel to suppress traumatic tendon heterotopic ossification.
AU - Haoyang Feng
AU - Kai Ang
AU - Zengfa Deng
AU - Chonghe Cui
AU - Jialan Chen
AU - Nanfeng Huang
AU - Yimei Feng
AU - Jimei Zhang
AU - Danlin Li
AU - Zhen Kong
AU - Zicheng Cai
AU - Yongjian Sun
AU - Yusheng Yang
PY - 2026
DA - 2026/10/14
JO - Bioactive materials
DO - 10.1016/j.bioactmat.2026.10.006
UR - https://europepmc.org/article/MED/42927122
AB - Traumatic heterotopic ossification (HO) is a debilitating complication of tendon injury, yet its pathogenic mechanisms remain elusive and effective preventive strategies are lacking. Here, we identify a glycometabolic-epigenetic axis that drives HO progression. Single-cell profiling and functional analyses reveal that hypoxic chondrocytes undergo glycolytic reprogramming, leading to lactate accumulation and transfer into tendon-derived mesenchymal stem cells (TD-MSCs) through MCT1. This metabolic coupling promotes P300-dependent histone H3 lysine 18 lactylation (H3K18la), activating osteogenic programs characterized by Col6a1, Zhx3, Lox and Vdr expression and thereby facilitating pathological endochondral ossification. Guided by this mechanism, we develop a tendon-adhesive hydrogel (GelHA-A485@Exos) that integrates mechanical repair with targeted epigenetic modulation. MSC-derived exosomes enable localized delivery of the P300 inhibitor A485, suppressing H3K18la and aberrant osteogenic activation, while the hydrogel scaffold enhances tendon regeneration. In vivo and in vitro studies demonstrate that GelHA-A485@Exos promotes tendon healing while preventing HO formation. Our findings establish metabolic-epigenetic communication as a central regulator of traumatic HO and provide a translational therapeutic strategy for its clinical prevention.
SN - 2452-199X
ER -