PDL1 triggered by binding eIF3I contributes to the amelioration of diabetes-associated wound healing defects by regulating IRS4.

Persistent chronic inflammation and delayed epithelialization lead to stalled healing in diabetic ulcers (DUs). PDL1 shows anti-inflammatory and proliferative activities in healing defects, while its function in DU pathogenesis remains unknown. Lower levels of PDL1 were found in DU tissues, and exogenous PDL1 has therapeutic effects in healing process by accelerating re-epithelialization and attenuating prolonged inflammation, which contributed to the delayed wound closure. We detected the downstream effectors of PDL1 using transcriptional profiles, and screened the interacting proteins by IP-MS and Co-IP assays. The biological functions of eIF3I-PDL1-IRS4 axis were tested both in vivo and in vitro. Finally, we validated the expression levels of eIF3I, PDL1, and IRS4 in DU tissues from human clinical samples by immunohistochemistry staining. Mechanistically, PDL1 binds to eIF3I and promotes cutaneous diabetic wound healing by downregulating IRS4. These findings identify the eIF3I-PDL1-IRS4 axis contributes to wound healing defects, which can serve as a potential therapeutic target in DUs.