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

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

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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