AhR deficiency exacerbates inflammation in diabetic wounds via impaired mitophagy and cGAS-STING-NLRP3 activation: Therapeutic potential of hydrogels loaded with FICZ
Delayed healing of diabetic foot ulcers (DFUs) is driven by chronic inflammation and mitochondrial dysfunction. We identify the aryl hydrocarbon receptor (AhR) as a key regulator of immune and mitochondrial homeostasis in diabetic wounds. AhR expression was elevated in macrophages from human and mur...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-10-01
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| Series: | Materials Today Bio |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590006425006891 |
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| author | Yingying Wang Tianyi Ni Qian Zhang Zibo Xu Zhechen Zhu Jiaheng Xie Min Yi Liying Tu Zexiong Cheng Yiwen Gao Haowen Xu Wei Yan Jingping Shi |
| author_facet | Yingying Wang Tianyi Ni Qian Zhang Zibo Xu Zhechen Zhu Jiaheng Xie Min Yi Liying Tu Zexiong Cheng Yiwen Gao Haowen Xu Wei Yan Jingping Shi |
| author_sort | Yingying Wang |
| collection | DOAJ |
| description | Delayed healing of diabetic foot ulcers (DFUs) is driven by chronic inflammation and mitochondrial dysfunction. We identify the aryl hydrocarbon receptor (AhR) as a key regulator of immune and mitochondrial homeostasis in diabetic wounds. AhR expression was elevated in macrophages from human and murine DFUs. In AhR knockout mice, loss of AhR impaired M2 macrophage polarization and enhanced NLRP3 inflammasome activation via the cGAS–STING pathway. Mechanistically, AhR deficiency suppressed mitophagy, causing mitochondrial DNA leakage and sustained inflammatory signaling. To target this axis, we developed a FICZ-loaded GelMA hydrogel (GelMA–FICZ). Local application of GelMA–FICZ restored mitochondrial function, inhibited inflammasome activation, and significantly improved wound healing in diabetic mice. This study reveals a critical AhR–mitochondria–inflammasome pathway in DFUs and suggests a novel biomaterial-based immunomodulatory therapy for diabetic wound repair. |
| format | Article |
| id | doaj-art-310e7a8514e946d093ccaa36d75be04f |
| institution | DOAJ |
| issn | 2590-0064 |
| language | English |
| publishDate | 2025-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Materials Today Bio |
| spelling | doaj-art-310e7a8514e946d093ccaa36d75be04f2025-08-20T02:48:38ZengElsevierMaterials Today Bio2590-00642025-10-013410211910.1016/j.mtbio.2025.102119AhR deficiency exacerbates inflammation in diabetic wounds via impaired mitophagy and cGAS-STING-NLRP3 activation: Therapeutic potential of hydrogels loaded with FICZYingying Wang0Tianyi Ni1Qian Zhang2Zibo Xu3Zhechen Zhu4Jiaheng Xie5Min Yi6Liying Tu7Zexiong Cheng8Yiwen Gao9Haowen Xu10Wei Yan11Jingping Shi12Department of Burn and Plastic Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210000, Jiangsu, PR ChinaDepartment of Burn and Plastic Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210000, Jiangsu, PR ChinaDepartment of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210000, Jiangsu, PR ChinaPeking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100000, PR ChinaDepartment of Burn and Plastic Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210000, Jiangsu, PR ChinaDepartment of Plastic Surgery, Xiangya Hospital, Central South University, Changsha, PR ChinaDepartment of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, 210000, Jiangsu, PR ChinaDepartment of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, 210000, Jiangsu, PR ChinaDepartment of Burn and Plastic Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210000, Jiangsu, PR ChinaDepartment of Burn and Plastic Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210000, Jiangsu, PR ChinaDepartment of Burn and Plastic Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210000, Jiangsu, PR ChinaDepartment of Burn and Plastic Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210000, Jiangsu, PR China; Corresponding author.Department of Burn and Plastic Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210000, Jiangsu, PR China; Corresponding author.Delayed healing of diabetic foot ulcers (DFUs) is driven by chronic inflammation and mitochondrial dysfunction. We identify the aryl hydrocarbon receptor (AhR) as a key regulator of immune and mitochondrial homeostasis in diabetic wounds. AhR expression was elevated in macrophages from human and murine DFUs. In AhR knockout mice, loss of AhR impaired M2 macrophage polarization and enhanced NLRP3 inflammasome activation via the cGAS–STING pathway. Mechanistically, AhR deficiency suppressed mitophagy, causing mitochondrial DNA leakage and sustained inflammatory signaling. To target this axis, we developed a FICZ-loaded GelMA hydrogel (GelMA–FICZ). Local application of GelMA–FICZ restored mitochondrial function, inhibited inflammasome activation, and significantly improved wound healing in diabetic mice. This study reveals a critical AhR–mitochondria–inflammasome pathway in DFUs and suggests a novel biomaterial-based immunomodulatory therapy for diabetic wound repair.http://www.sciencedirect.com/science/article/pii/S2590006425006891Aryl hydrocarbon receptor (AhR)Macrophage polarizationMitophagyGelMA hydrogel |
| spellingShingle | Yingying Wang Tianyi Ni Qian Zhang Zibo Xu Zhechen Zhu Jiaheng Xie Min Yi Liying Tu Zexiong Cheng Yiwen Gao Haowen Xu Wei Yan Jingping Shi AhR deficiency exacerbates inflammation in diabetic wounds via impaired mitophagy and cGAS-STING-NLRP3 activation: Therapeutic potential of hydrogels loaded with FICZ Materials Today Bio Aryl hydrocarbon receptor (AhR) Macrophage polarization Mitophagy GelMA hydrogel |
| title | AhR deficiency exacerbates inflammation in diabetic wounds via impaired mitophagy and cGAS-STING-NLRP3 activation: Therapeutic potential of hydrogels loaded with FICZ |
| title_full | AhR deficiency exacerbates inflammation in diabetic wounds via impaired mitophagy and cGAS-STING-NLRP3 activation: Therapeutic potential of hydrogels loaded with FICZ |
| title_fullStr | AhR deficiency exacerbates inflammation in diabetic wounds via impaired mitophagy and cGAS-STING-NLRP3 activation: Therapeutic potential of hydrogels loaded with FICZ |
| title_full_unstemmed | AhR deficiency exacerbates inflammation in diabetic wounds via impaired mitophagy and cGAS-STING-NLRP3 activation: Therapeutic potential of hydrogels loaded with FICZ |
| title_short | AhR deficiency exacerbates inflammation in diabetic wounds via impaired mitophagy and cGAS-STING-NLRP3 activation: Therapeutic potential of hydrogels loaded with FICZ |
| title_sort | ahr deficiency exacerbates inflammation in diabetic wounds via impaired mitophagy and cgas sting nlrp3 activation therapeutic potential of hydrogels loaded with ficz |
| topic | Aryl hydrocarbon receptor (AhR) Macrophage polarization Mitophagy GelMA hydrogel |
| url | http://www.sciencedirect.com/science/article/pii/S2590006425006891 |
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