DNMT1-targeted macrophages delivering drug-loaded nanoparticles attenuate heart allograft fibrosis via PTPRD-STAT3/6 axis
- 1Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Organ Transplantation Clinical Medical Research Center of Hubei Province, Wuhan, China
- 2School of Pharmacy, Tongji Medical Colloge, Huazhong University of Science and Technology, Wuhan, China
- 3Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Abstract
Distinct macrophage activation states play key roles in the formation and progression of heart allograft fibrosis. However, the exact molecular mechanisms that regulate the balance between inflammatory and pro-fibrotic macrophage responses during fibrosis remain poorly understood. Identifying and targeting the key molecule that regulates the differentiation of inflammatory and pro-fibrotic macrophages might be a pivotal strategy for mitigating fibrosis and prolonging allograft survival. Here, using single-cell sequencing analysis of human heart allografts fibrosis patient samples, we identified a population of macrophages that undergo epigenetic reprogramming through DNA methylation regulated by DNA methyltransferase DNMT1. DNMT1 small-molecule inhibitor 5-AzaC significantly attenuated graft fibrosis and prolonged allograft survival by inhibiting both inflammation and excessive tissue repair. Mechanistically, DNMT1-targeted macrophages suppress the DNA methylation level of the CpG island in the first intron of PTPRD, promoting PTPRD expression, which in turn inhibits the activity of STAT3 and STAT6 pathways, thereby suppressing the differentiation of inflammation and pro-fibrotic macrophages. Based on this, we developed a macrophage-targeted nanocarrier, MV/PEG-LPs, to load 5-AzaC, thereby enhancing its therapeutic precision for allograft fibrosis. Our results reveal a novel target, DNA methylation in macrophages, for the treatment of fibrosis-related diseases.
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BibTeX
@article{yuan2026dnmt1targeted,
title = {{DNMT1-targeted macrophages delivering drug-loaded nanoparticles attenuate heart allograft fibrosis via PTPRD-STAT3/6 axis}},
author = {Naonao Yuan and Zhibo Ma and Zihan Xue and Qingwen Li and Xi Zhou and Jing Liu and Yanping Lin and Shiqi Gu and Sichuan Yi and Yao Lu and Peixiang Lan},
journal = {Cell Death Discovery},
year = {2026},
month = aug,
doi = {10.1038/s41420-026-03295-5},
url = {https://doi.org/10.1038/s41420-026-03295-5},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - DNMT1-targeted macrophages delivering drug-loaded nanoparticles attenuate heart allograft fibrosis via PTPRD-STAT3/6 axis
AU - Naonao Yuan
AU - Zhibo Ma
AU - Zihan Xue
AU - Qingwen Li
AU - Xi Zhou
AU - Jing Liu
AU - Yanping Lin
AU - Shiqi Gu
AU - Sichuan Yi
AU - Yao Lu
AU - Peixiang Lan
PY - 2026
DA - 2026/08/07
JO - Cell Death Discovery
DO - 10.1038/s41420-026-03295-5
UR - https://doi.org/10.1038/s41420-026-03295-5
AB - Distinct macrophage activation states play key roles in the formation and progression of heart allograft fibrosis. However, the exact molecular mechanisms that regulate the balance between inflammatory and pro-fibrotic macrophage responses during fibrosis remain poorly understood. Identifying and targeting the key molecule that regulates the differentiation of inflammatory and pro-fibrotic macrophages might be a pivotal strategy for mitigating fibrosis and prolonging allograft survival. Here, using single-cell sequencing analysis of human heart allografts fibrosis patient samples, we identified a population of macrophages that undergo epigenetic reprogramming through DNA methylation regulated by DNA methyltransferase DNMT1. DNMT1 small-molecule inhibitor 5-AzaC significantly attenuated graft fibrosis and prolonged allograft survival by inhibiting both inflammation and excessive tissue repair. Mechanistically, DNMT1-targeted macrophages suppress the DNA methylation level of the CpG island in the first intron of PTPRD, promoting PTPRD expression, which in turn inhibits the activity of STAT3 and STAT6 pathways, thereby suppressing the differentiation of inflammation and pro-fibrotic macrophages. Based on this, we developed a macrophage-targeted nanocarrier, MV/PEG-LPs, to load 5-AzaC, thereby enhancing its therapeutic precision for allograft fibrosis. Our results reveal a novel target, DNA methylation in macrophages, for the treatment of fibrosis-related diseases.
SN - 2058-7716
ER -