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. 2025 Nov 15;39(21):e71103.
doi: 10.1096/fj.202501580RR.

UCMSCs-Derived Exosomal circHIPK3 Restrains Oxidative Stress and Inflammation by Downregulating the Stability of HMGB1 mRNA via Recruiting UPF1 in Diabetes Foot Ulcer

Nan-Fang Pan  1 , Shao-Wen Weng  2 , Shi-Shuai Lin  1 , Wei-Cheng Xu  3 , Jia Fu  3 , Zun-Hong Liang  1
Affiliations

UCMSCs-Derived Exosomal circHIPK3 Restrains Oxidative Stress and Inflammation by Downregulating the Stability of HMGB1 mRNA via Recruiting UPF1 in Diabetes Foot Ulcer

Nan-Fang Pan et al. FASEB J. .

Abstract

Excessive oxidative stress and inflammation in human umbilical vein endothelial cells (HUVECs) are significant barriers to wound healing in diabetic foot ulcers (DFUs). Umbilical cord mesenchymal stem cells (UCMSCs)-derived exosomal circular RNA homeodomain-interacting protein kinase three (circHIPK3) exerts protective effects on HUVECs under high-glucose (HG) conditions. Our objective was to elucidate the downstream mechanisms through which UCMSCs-derived exosomal circHIPK3 modulates oxidative stress and inflammation in cellular and mice models of DFU. The type II diabetic db/db mice model, HG-induced HUVECs, and HG-treated human dermal microvascular endothelial cells (HDMECs) were used to investigate the mechanism of UCMSCs-derived exosomal circHIPK3. HG induced oxidative stress and inflammation in HUVECs, which were attenuated by UCMSCs-derived exosomal circHIPK3. Next, UCMSCs-derived exosomal circHIPK3 reduced HG-induced HUVECs' oxidative stress and inflammation by downregulating high mobility group box 1 (HMGB1). Furthermore, up-frameshift protein 1 (UPF1) reduced the stability of HMGB1 mRNA through direct interaction. Additionally, UCMSCs-derived exosomal circHIPK3 alleviated HG-induced oxidative stress and inflammation in HUVECs by upregulating UPF1 expression. UPF1 protected HUVECs from HG-induced oxidative stress and inflammation by decreasing HMGB1 mRNA stability. UCMSCs-derived exosomal circHIPK3 also enhanced wound healing in a DFU mice model and reduced oxidative stress and inflammation in HG-treated HDMECs. Overall, UCMSCs-derived exosomal circHIPK3 suppressed HG-stimulated oxidative stress and inflammation, thereby promoting wound healing in both cellular and animal DFU models through the UPF1/HMGB1 axis. These findings suggested that the UCMSCs-derived exosomal circHIPK3/UPF1/HMGB1 axis represents a promising therapeutic target for treating DFU.

Keywords: HMGB1; HUVECs; UCMSCs‐derived exosomal circHIPK3; UPF1; inflammation; oxidative stress.

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References

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