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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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-10-01
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| Series: | Materials Today Bio |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590006425006891 |
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| Summary: | 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. |
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| ISSN: | 2590-0064 |