C1q/TNF-related protein-9 promotes diabetic wound healing by enhancing dendritic cell efferocytosis via the ATF3/SLC7A11 signaling axis.

Chronic wound healing, particularly in diabetic wounds, remains a global challenge. The delayed or even stagnant healing process imposes a substantial burden on both society and individuals. A critical challenge lies in effectively reducing inflammatory levels and promoting vascular remodeling. As an adipokine, C1QTNF9 (CTRP9) has been demonstrated to suppress inflammatory responses under various pathological conditions. In diabetic wound healing, CTRP9 facilitates the proliferation, differentiation, and migration of keratinocytes, yet its specific regulatory mechanisms on local inflammation remain unclear. Transcriptomic analysis of diabetic wounds revealed significantly reduced CTRP9 transcription levels in non-healing wounds. Animal experiments showed lower CTRP9 expression in the skin tissues of diabetic mice compared to normal mice, suggesting a close association between CTRP9 and wound healing. Subsequent local supplementation of CTRP9 in diabetic mouse wounds significantly accelerated healing to near-normal levels. Notably, SLC7A11 (also known as xCT)-a key protein linked to impaired efferocytosis in dendritic cells at diabetic wounds-was downregulated by CTRP9, while CTRP9 enhanced efferocytic efficiency. ATF3, a transcriptional repressor of SLC7A11 involved in ferroptosis regulation, has not been previously explored in dendritic cell efferocytosis. This study found that ATF3 knockdown upregulated SLC7A11 expression and attenuated CTRP9-mediated efferocytosis enhancement, indicating ATF3 as a critical pathway through which CTRP9 regulates SLC7A11. Furthermore, CTRP9 enhances glycolysis to produce lactate, thereby providing energy support for dendritic cell efferocytosis. In summary, this study demonstrates that CTRP9, as an anti-inflammatory factor, promotes diabetic wound healing by enhancing dendritic cell efferocytosis and reducing local inflammation, offering a promising therapeutic strategy.