MicroRNA-221-3p inhibits the inflammatory response of keratinocytes by regulating the DYRK1A/STAT3 signaling pathway to promote wound healing in diabetes

Abstract

Diabetic foot ulcer (DFU), a serious complication of diabetes, remains a clinical challenge. MicroRNAs affect inflammation and may have therapeutic value in DFU. Here, we find that an miR-221-3p mimic reduces the inflammatory response and increases skin wound healing rates in a mouse model of diabetes, whereas miR-221-3p knockout produced the opposite result. In human keratinocytes cells, miR-221-3p suppresses the inflammatory response induced by high glucose. The gene encoding DYRK1A is a target of miR-221-3p. High glucose increases the expression of DYRK1A, but silencing DYRK1A expression decreases high glucose–induced inflammatory cytokine release via dephosphorylation of STAT3, a substrate of DYRK1A. Application of miR-221-3p mimic to human keratinocytes cells not only decreases DYRK1A expression but also inhibits high glucose–induced production of inflammatory cytokines to promote wound healing. This molecular mechanism whereby miR-221-3p regulates inflammation through the DYRK1A/STAT3 signaling pathway suggests targets and therapeutic approaches for treating DFU.

An update on chronic complications of diabetes mellitus: from molecular mechanisms to therapeutic strategies with a focus on metabolic memory

“…In the majority of studies exploring diabetes and its chronic complications, a hyperglycemic exposure period of 48–72 h is typically considered representative of chronic hyperglycemia with long-term deleterious effects. This holds true for conditions such as DKD, DF, and diabetic cardiomyopathy (Hu et al 2024 ; Wang et al 2024 ; Li, et al 2024 ; Song et al 2023 ; Feng et al 2023 ). However, it is worth noting that the duration of exposure to high glucose, as well as the periods of exposure to normal glucose, vary significantly across studies examining metabolic memory.…”

Translational Challenges in Drug Therapy and Delivery Systems for Treating Chronic Lower Extremity Wounds

“…Aside from introducing engineer cells to DFUs, gene silencing therapy using micro-RNA (miR) was also explored for wound healing in murine diabetic wounds. Injection of miR-221-3p into these wounds demonstrated enhanced healing by regulating signaling pathways in keratinocytes [ 165 ].…”