Autophagosomes Defeat Ferroptosis by Decreasing Generation and Increasing Discharge of Free Fe²⁺ in Skin Repair Cells to Accelerate Diabetic Wound Healing

Abstract

Ferroptosis plays an essential role in the development of diabetes and its complications, suggesting potential therapeutic strategies targeting ferroptosis. Secretory autophagosomes (SAPs) carrying cytoplasmic cargoes have been recognized as novel nano‐warrior to defeat diseases. Here, it is hypothesized that SAPs derived from human umbilical vein endothelial cells (HUVECs) can restore the function of skin repair cells by inhibiting ferroptosis to promote diabetic wound healing. High glucose (HG)‐caused ferroptosis in human dermal fibroblasts (HDFs) is observed in vitro, which results in impaired cellular function. SAPs successfully inhibit ferroptosis in HG‐HDFs, thereby improving their proliferation and migration. Further research show that the inhibitory effect of SAPs on ferroptosis resulted from a decrease in endoplasmic reticulum (ER) stress‐regulated generation of free ferrous ions (Fe2+) in HG‐HDFs and an increase in exosome release to discharge free Fe2+ from HG‐HDFs. Additionally, SAPs promote the proliferation, migration, and tube formation of HG‐HUVECs. Then the SAPs are loaded into gelatin‐methacryloyl (GelMA) hydrogels to fabricate functional wound dressings. The results demonstrate the therapeutic effect of Gel‐SAPs on diabetic wounds by restoring the normal behavior of skin repair cells. These findings suggest a promising SAP‐based strategy for the treatment of ferroptosis‐associated diseases.

Recent advances of hydrogels as smart dressings for diabetic wounds

“…Studies have shown that SAPs can promote the proliferation, migration, and tube formation of HG-HUVECs by reducing Fe 2+ accumulation and ROS production. 166 Another way to inhibit iron death is to use iron chelators such as deferoxamine (DFO) on the wound. Shao and colleagues prepared a gelatin microsphere containing DFO (DFO@G) through a reaction between the boronic acid group of 3-carboxy-4-fluorophenylboronic acid grafted quaternized CS and the hydroxyl group of PVA.…”

Autophagy, Pyroptosis and Ferroptosis are Rising Stars in the Pathogenesis of Diabetic Nephropathy

“…More and more studies have shown that HG induces ferroptosis of endothelial cells participates in diabetes retinopathy, 89 diabetes atherosclerosis, 97 diabetic wounds, 98 and diabetes-related limb ischemia. 99 Previous studies have shown that glomerular endothelial cells ferroptosis plays an important role in the pathophysiological process of DN.…”

The Role of p53 in Regulating Chronic Inflammation and PANoptosis in Diabetic Wounds

“…In the context of DFU, ferroptosis expression is elevated [153], and has been demonstrated to mitigate ferroptosis and enhance healing [154]. The TP53 gene, a central player in DW, exhibits increased expression in diabetic foot tissue compared to healthy tissue [155].…”