New enzyme target and asiatic acid derivatives promote diabetic wound healing in early studies

Researchers identify the metabolic enzyme FBP1 as a key obstacle in diabetic skin repair and develop a novel topical gel based on a natural compound derivative, showing promising results in mice and potentially paving the way for new treatments for stubborn diabetic wounds.

A metabolism enzyme better known for its role in glucose production than skin repair may be helping to keep diabetic wounds open. Researchers at Shenyang Pharmaceutical University report that blocking fructose-1,6-bisphosphatase 1, or FBP1, helped damaged skin cells recover and allowed a topical gel built around a modified plant compound to speed healing in diabetic mice. The finding matters because delayed wound repair in diabetes can progress to stubborn ulcers and, in severe cases, amputation.

Published in the Journal of Advanced Research in December 2025 and later indexed across major research databases, the study argues that one neglected part of diabetic wound failure lies in keratinocytes, the cells responsible for rebuilding the skin surface. To mimic the hostile environment around a diabetic wound, the researchers injured HaCaT keratinocytes with methylglyoxal, a reactive by-product associated with high blood sugar. RNA sequencing in that model found 1,375 genes upregulated and 724 downregulated, with FBP1 emerging as one of the genes pushed sharply higher.

The team then asked whether FBP1 was simply a sign of cell stress or an active obstacle to repair. According to the paper’s abstracts on PubMed and ScienceDirect, increasing FBP1 suppressed keratinocyte growth and movement, both essential for wound closure, while reducing it had the opposite effect. That turned the enzyme from a biochemical curiosity into a plausible drug target for diabetic wounds.

To find a blocker, the scientists combined computer-based screening with laboratory testing and landed on asiatic acid, a natural triterpenoid from Centella asiatica. A Chinese report on the paper said the compound fitted into FBP1’s binding pocket with a docking energy of -7.15 kcal/mol and inhibited the enzyme with an IC50 of 2.50 μM. That was stronger than AMP, the enzyme’s natural regulator, which the same account put at 7.97 μM. The journal abstract likewise describes asiatic acid as a potent FBP1 inhibitor identified through virtual and experimental screening.

The researchers did not stop there, because asiatic acid itself is not an ideal topical medicine. Its chemistry limits how well it penetrates skin, so they built several derivatives carrying hydrogen sulphide donors and selected one, known as AA4, as the lead candidate. PubMed and ScienceDirect say AA4 works through a dual mechanism: it still inhibits FBP1 directly, but the hydrogen sulphide element also drives down the amount of FBP1 protein in cells. In the authors’ account, that two-pronged attack restored AKT/mTOR/HIF-1α/uPAR signalling, which is linked to cell growth and migration, while cutting apoptosis markers tied to cell death, including Bcl-2/Bax/Caspase-3.

In diabetic mice, the candidate was delivered in a topical gel. The study summaries say AA4 markedly improved closure of full-thickness wounds, promoted epidermal regeneration and collagen deposition, and reduced inflammatory activity in the damaged tissue. The Chinese write-up adds that the treatment also shifted macrophages away from a pro-inflammatory M1 state towards the more reparative M2 state. By day seven, that report said AA4-treated wounds had closed far more than untreated diabetic wounds, with higher-dose gel outperforming both unmodified asiatic acid and AMP.

The paper remains an early-stage result, and there is no evidence yet that AA4 can treat diabetic foot ulcers in patients. Even so, it points towards a broader rethink of why these wounds persist. Rather than viewing diabetic wound failure chiefly as a problem of blood supply or infection control, the study suggests that a metabolic enzyme inside keratinocytes may itself be a therapeutic choke point. JoVE Visualize later distilled the idea by saying that targeting FBP1 “shows promise for diabetic wound healing”, while publication records on ResearchGate and AbleSci confirm the paper’s recent appearance in the Journal of Advanced Research. For now, AA4 looks less like a ready-made medicine than a carefully engineered proof of concept for one of diabetes’ hardest complications to treat.