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

  • J Adv Res. 2025 Dec 8:S2090-1232(25)00993-2. doi: 10.1016/j.jare.2025.12.003.
Shenglin Wang  1 ,  Tongtong Ye  2 ,  Lihao Shi  1 ,  Chao Zheng  3 ,  Weirenbo Wang  1 ,  Lin Dong  4 ,  Sisi Ou  5 ,  Siqing Li  2 ,  Junxia Wu  2 ,  Fanxing Xu  6 ,  Huiming Hua  7 ,  Maosheng Cheng  8 ,  Dahong Li  9
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3. Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON M5T 1R8, Canada; Departments of Psychiatry, Chemistry, Pharmacology and Toxicology, University of Toronto, Toronto, ON M5T-1R8, Canada.
  • 4. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 5. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 6. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
  • 7. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
  • 8. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
  • 9. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: [email protected].
PMID: 41371402 DOI: 10.1016/j.jare.2025.12.003
Abstract

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.

Keywords
Asiatic acid; Diabetic wound healing; FBP1; Hydrogen sulfide.
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