Diabetes & Metabolism Journal

Original Articles

Complications
4-Octyl Itaconate Promotes Diabetic Wound Healing by Enhancing Pro-Resolving Macrophages via the Efferocytosis-MCT1-Lactate-GPR132 Pathway and Macrophage-Independent Synergistic Effects: Mengqin Tu, Xiaoli Zou, Xiaozhen Tan, Yijun Liu, Xinxu Ge, Yu Hu, Qiuyue Peng, Linlin Huang, Yan Zeng, Chunxia Jia, Man Guo, Jiao Chen, Yang Long, Yong Xu; Received September 21, 2024 Accepted July 2, 2025 Published online November 3, 2025; DOI: https://doi.org/10.4093/dmj.2024.0579 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub

Background
Diabetic foot ulcers are a severe diabetic complication causing poor healing. Itaconate, a tricarboxylicacid cycle byproduct, has been shown to improve wound healing. This study investigated the potential of 4-octyl itaconate (4-OI), an esterified derivative of itaconate, to modulate efferocytosis andmacrophage pro-resolving function to promote diabetic wound healing.
Methods
A diabetic mouse wound model was used. For in vitro analysis, RAW264.7 macrophages and apoptotic Jurkat cells were cocultured under high glucose (HG, 30 mM). To further evaluate the roles of macrophages, monocarboxylate transporter 1 (MCT1), and lactate in 4-OI-promoted diabetic wound healing, we used clodronate-liposomes (CLD-Lipo) to deplete macrophages, AZD3965 (an MCT1 inhibitors), telmisartan to validate our hypothesis.
Results
In diabetic mice, impaired apoptotic neutrophils clearance and persistent M1 activation delayed wound healing. 4-OI improved diabetic wound repair by enhancing efferocytosis, shifting macrophages toward M2 pro-resolving phenotype, and boosting angiogenesis. 4-OI showed a protective effect mediated by macrophages, while endothelial cells and neutrophils also played synergistic roles in diabetic wound healing. Moreover, 4-OI upregulated MCT1 which, in turn, increased release of lactate triggered by efferocytosis at the wound site. Lastly, we confirmed that pro-resolving effects of 4-OI onmacrophage function were mediated by promoting pro-resolving macrophage proliferation and polarization via efferocytosis-induced lactate release and subsequent activation of G protein-coupled receptor 132 (GPR132).
Conclusion
4-OI promotes diabetic wound healing through macrophage-dependent/independent mechanisms. Moreover, the protective effect of 4-OI on macrophage was mediated through MCT1-mediated lactate release triggered by efferocytosis and subsequent GRP132 activation.

Citations

Citations to this article as recorded by

Roles of efferocytosis in wound repair: Process, cells, and signals
Yilin Sun, Haiying Guo, Yang Bai, Jin Chen, Yuhong Li
Genes & Diseases.2026; 13(3): 101937. CrossRef

Complications
STING Promotes Renal Fibrosis of Diabetic Kidney Disease via ID1-Dependent Epithelial-Mesenchymal Transition: Hongya Wang, Xiaobing Mao, Yuqing Huang, Xiaozhen Tan, Yuling Yang, Mengting Huang, Zongzhe Jiang, Yang Long, Xia Fang, Yong Xu; Received October 18, 2024 Accepted May 30, 2025 Published online October 28, 2025; DOI: https://doi.org/10.4093/dmj.2024.0645 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Tubulointerstitial fibrosis (TIF) due to epithelial-mesenchymal transition (EMT) is an inseparable feature of diabetic renal fibrosis. Although stimulator of interferon genes (STING) has been shown to have potential in regulating EMT, whether and how it modulates EMT in diabetic kidney disease (DKD) mice remains unclear. Here, we investigated the role and the underlying mechanisms of STING-mediated EMT on TIF in DKD.
Methods
STING expression was detected in human renal biopsy tissues and serum samples with DKD. Mouse models with genetic deletion of STING or inhibition by a STING inhibitor (C176) were established to further investigate the functions of STING in vivo. The in vitro roles of STING were analyzed in human renal tubular epithelial (HK2) cells with STING overexpression or STING knockdown. RNA sequencing was used to explore the underlying mechanisms.
Results
STING was upregulated in the kidneys and serum from patients with DKD and negatively correlated with kidney function. STING deletion or pharmacologic inhibition with C176 ameliorated pathological lesions, renal function and fibrosis in mouse models of DKD. STING deficiency alleviated renal fibrosis in DKD mice via inhibiting EMT. Mechanistically, by RNA sequencing, inhibitor of differentiation 1 (ID1) was found to a downstream molecule of STING. Inhibition of ID1 on the basis of overexpression of STING could suppress EMT and renal fibrosis.
Conclusion
Our study provides evidence that STING deficiency relieves renal fibrosis by inhibiting ID1-mediated EMT and that inhibition of STING and ID1 has the potential therapeutic prospects for patients with DKD.

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