Investigation of the Efficacy and Mechanism of Monoacylglycerol Lipase Inhibitors in Diabetic Foot Ulcers.

Background/

Objectives

Wound healing proceeds in a timely and sequential manner through four well-defined phases: hemostasis, inflammation, proliferation, and remodeling. To explore the therapeutic efficacy and underlying mechanism of a novel monoacylglycerol lipase (MAGL) inhibitor (designated as MAGL11), a diabetic mouse model of skin wounds was established.

Methods

Wound healing progression was assessed via gross observation, while histological analyses (including HE staining and Masson staining) were conducted to evaluate tissue repair. Additionally, proteomic analysis and in vitro experiments were employed to validate the therapeutic effects and clarify the molecular mechanism of MAGL11.

Results

In vivo studies revealed that treatment with MAGL11 significantly accelerated wound closure in diabetic mice. Compared with the control group, MAGL11-treated wounds exhibited notably increased granulation tissue formation and collagen deposition, which was accompanied by a distinct anti-inflammatory effect. Results from proteomic profiling and in vitro experiments further demonstrated that MAGL11 exerted its pro-healing effects by promoting the activation of the Rap1/PI3K/Akt signaling pathway. Specifically, MAGL11 enhanced the migration and chemotaxis of fibroblasts (NIH3T3), human umbilical vein endothelial cells (HUVECs), and keratinocytes (HaCaT) while simultaneously inhibiting cellular apoptosis-all of which collectively contributed to improved wound healing.

Conclusions

These findings suggest that MAGL11 holds promise as a potential candidate for diabetic wound therapy, primarily through its ability to promote angiogenesis, fibroblast activation, and epithelial regeneration.