Discovery of FBP1 as novel therapeutic target and asiatic acid-hydrogen sulfide donors accelerate diabetic wound healing.

INTRODUCTION

Wound healing impairment is highly prevalent in diabetes and frequently progresses to serious complications, including refractory ulcers and necessitated amputations. RNA sequencing in methylglyoxal (MGO)-injured HaCaT cells implicated fructose-1,6-bisphosphatase 1 (FBP1) in suppressing keratinocyte proliferation and migration, identifying it as a potential therapeutic target.

OBJECTIVES

This study aimed to validate FBP1 as a therapeutic target for diabetic wounds and evaluate asiatic acid (AA) and its novel hydrogen sulfide (H2S)-donor derivatives, designed to enhance efficacy, as FBP1-targeted interventions.

METHODS

Target discovery was performed via transcriptomics in MGO-injured HaCaT cells, identifying FBP1 as a key regulator. Virtual screening of compound libraries was combined with experimental screening to discover AA as a potent FBP1 inhibitor. Based on AA's structure, novel H2S-donor derivatives were rationally designed and synthesized to enhance therapeutic properties. A topical AA4 gel was formulated and tested for its therapeutic impact on diabetic wound repair in mouse models.

RESULTS

AA was identified as a potent FBP1 inhibitor (IC50 = 2.5 μM). AA4, a synthesized H2S-donor derivative, exhibited dual mechanisms: direct FBP1 enzymatic inhibition and H2S-mediated FBP1 downregulation. This synergistically restored proliferation pathways (AKT/mTOR/HIF-1α/uPAR) and reduced apoptosis (Bcl-2/Bax/Caspase-3). Topical AA4 gel markedly enhanced wound closure rates in diabetic mice, primarily through promoting epidermal regeneration and collagen deposition.

CONCLUSION

This study validates FBP1 targeting as a feasible strategy to address diabetic wound healing. It establishes AA-H2S donor derivatives, particularly AA4 acting via dual FBP1 targeting, as an encouraging precision therapy for diabetic wound healing.