Chronic wounds are among the most stubborn complications of diabetes, trapping millions of patients in cycles of inflammation, infection and tissue breakdown that standard dressings cannot resolve. Now a research team writing in the Journal of Advanced Research has unveiled a bio-inspired supramolecular hydrogel that attacks one of the hidden culprits behind these non-healing wounds: ferroptosis, an iron-driven form of regulated cell death that destroys the endothelial cells needed to rebuild blood vessels. By combining a natural flavonoid from Chinese skullcap with a self-assembling licorice molecule, gelatin and zinc ions, the researchers created a wound dressing that in diabetic rats closed nearly 96 percent of full-thickness skin wounds within nine days, dramatically outperforming the drug or the scaffold alone.
The scientific premise rests on a growing appreciation of ferroptosis as a driver of diabetic pathology. Unlike apoptosis, ferroptosis kills cells through runaway lipid peroxidation: reactive oxygen species accumulate, iron metabolism goes awry, and the fatty membranes of cells are oxidized until they rupture. In high-glucose environments resembling diabetic tissue, the researchers showed that human umbilical vein endothelial cells, the workhorses of new blood vessel formation, suffered precisely this fate. Exposure to 33 millimolar glucose for 48 hours reduced cell viability, crippled migration in scratch and Transwell assays, and simplified the vascular networks the cells could form on Matrigel. At the molecular level, the high-glucose conditions suppressed GPX4, the glutathione-dependent enzyme that normally detoxifies lipid peroxides, while raising levels of NCOA4, a mediator of ferritinophagy that liberates iron from storage, and TFR1, the transferrin receptor that imports more iron. The result was a measurable surge in intracellular reactive oxygen species, malondialdehyde, a canonical marker of lipid peroxidation, and free ferrous iron.
Into this pathological picture the team introduced baicalein, a 5,6,7-trihydroxyflavone extracted from the roots of Scutellaria baicalensis, a plant long used in traditional East Asian medicine. The compound’s triple hydroxyl arrangement gives it exceptional antioxidant capacity, allowing it to neutralize reactive oxygen species directly and to chelate ferrous iron into stable complexes that cannot participate in Fenton reactions, the chemistry that converts hydrogen peroxide into the most destructive hydroxyl radicals. In the new experiments, baicalein at 20 micromolar, a concentration shown to be non-toxic up to 100 micromolar, largely restored endothelial viability, migration and tube formation under both high-glucose stress and treatment with RSL-3, a chemical that induces ferroptosis by covalently inactivating GPX4. The drug upregulated GPX4, dampened NCOA4 and TFR1, and pushed down cellular levels of reactive oxygen species, malondialdehyde and free iron, confirming that its protective effect operates specifically through the ferroptosis machinery rather than through some generic stress response.
The mechanistic core of the study lies in the Keap1/NRF2/HIF-1α signaling axis. Under resting conditions, the protein Keap1 binds NRF2, the master transcriptional regulator of antioxidant defense, and tags it for degradation. Oxidative stress normally pries this pair apart, freeing NRF2 to enter the nucleus and activate antioxidant response elements in genes such as GPX4. The researchers found that high glucose or RSL-3 pushed the system the wrong way, elevating Keap1 while suppressing NRF2 and, downstream, HIF-1α, the oxygen-sensing transcription factor that drives vascular endothelial growth factor production and angiogenesis. Molecular docking predicted that baicalein binds the Kelch domain of Keap1 with a favorable energy of minus 8.73 kilocalories per mole, forming hydrogen bonds with residues including VAL-420, VAL-512 and VAL-467. Co-immunoprecipitation then confirmed that baicalein promotes dissociation of the Keap1–NRF2 complex in cells. When the team knocked down NRF2 with lentiviral shRNA, or blocked it pharmacologically with ML385, baicalein’s anti-ferroptotic protection collapsed, GPX4 fell, iron import genes rose, and oxidative markers climbed, demonstrating that NRF2 is essential to the drug’s action and that NRF2 in turn sustains HIF-1α expression through a validated antioxidant response element in the HIF1A enhancer.
Translating this chemistry into a clinically usable dressing required solving a stubborn formulation problem: baicalein is poorly soluble in water, so free drug applied to a wound would never reach therapeutic concentrations. The team’s solution borrows from plant defense chemistry itself. Glycyrrhizic acid, a natural triterpenoid from licorice, self-assembles in aqueous solution into nanofibers that encapsulate baicalein, dramatically enhancing its solubility and enabling sustained release. These nanofibers were then complexed with gelatin and zinc ions at 40 degrees Celsius and gelled overnight, producing a dual physically cross-linked network held together by metal-coordination bonds between zinc and the carboxyl groups of glycyrrhizic acid and by hydrogen bonds between gelatin and the nanofibers. Infrared spectroscopy tracked the structural evolution, showing a broadened, shifted O–H peak at 3267 inverse centimeters indicative of the hydrogen-bonded network and the disappearance of characteristic baicalein-glycyrrhizic acid peaks upon zinc coordination.
Mechanical testing revealed a material well matched to living tissue. Rheology confirmed solid-dominated viscoelasticity, with the storage modulus exceeding the loss modulus across the tested frequency range, and the formulation containing 0.4 percent baicalein-glycyrrhizic acid nanofibers showed the highest storage modulus and greatest critical strain. Uniaxial compression yielded a Young’s modulus of about 33 kilopascals with fracture at 42 percent strain, soft enough to deform with skin, while lap-shear testing on porcine skin recorded an adhesive strength of roughly 62 kilopascals, enough to keep the patch anchored through joint flexion. The hydrogel also proved environmentally responsive. At physiological pH 7.4 it swelled to 186 percent of its dry weight, but at the acidic pH 5.5 characteristic of diabetic wounds, protonation of carboxyl groups compacted the network and limited swelling to 106 percent. Drug release was correspondingly slower in acid, extending baicalein retention exactly where diabetic wounds need it most, although matrix metalloproteinase-9 in simulated wound fluid accelerated degradation, a property that could allow the dressing to yield its payload as it dissolves in the enzyme-rich wound bed.
Safety and antimicrobial performance rounded out the preclinical profile. Live-dead staining and proliferation assays showed the composite hydrogel actually promoted endothelial cell growth, hemolysis rates stayed below the 5 percent safety threshold, and histological examination of heart, liver, spleen, lung and kidney tissue from treated rats revealed no pathological changes. Released baicalein is metabolized locally and systemically by glucuronidation and sulfation and cleared renally, limiting systemic exposure. Against Staphylococcus aureus and Escherichia coli, the two flagship wound pathogens, the components showed only modest activity individually, but the full composite achieved a bactericidal rate exceeding 70 percent against S. aureus, a synergy attributed to baicalein and glycyrrhizic acid disrupting bacterial walls while zinc ions inhibit metabolic enzymes. When cells were challenged with RSL-3, the hydrogel reduced reactive oxygen species, malondialdehyde and ferrous iron more effectively than any other formulation, approaching the performance of Ferrostatin-1, a benchmark ferroptosis inhibitor, and it also blunted hydrogen peroxide-induced apoptosis by activating the PI3K/Akt survival pathway.
The decisive test came in diabetic rats. The team induced diabetes with streptozotocin, excised one-centimeter full-thickness wounds on the animals’ backs, and treated them with phosphate buffer, free baicalein, baicalein-glycyrrhizic acid nanofibers, the gelatin-zinc scaffold without drug, or the complete composite. By day nine the full hydrogel had closed 96.4 percent of wound area, compared with 89.1 percent for the drug-free scaffold, 84.6 percent for the nanofibers alone and 76.5 percent for free baicalein. Hematoxylin and eosin staining showed reduced wound width and complete epithelialization in the composite group, while Masson’s trichrome revealed abundant, well-organized collagen deposition. Immunofluorescence for CD31 and alpha-smooth muscle actin documented a surge in mature new blood vessels, and immunohistochemistry confirmed the molecular signature seen in the dish: GPX4 up, NCOA4 and TFR1 down, Keap1 suppressed, and both NRF2 and HIF-1α elevated. Tumor necrosis factor-alpha levels fell as well, pointing to a calming of the chronic inflammation that normally stalls diabetic repair.
The work, led by Haiting Zou, Qian Tan and colleagues at Nanjing institutions, positions the baicalein-loaded glycyrrhizic acid hydrogel as a multifunctional platform that simultaneously fights infection, quenches oxidative stress, blocks ferroptotic endothelial death and stimulates revascularization, all from a single bio-derived dressing. Compared with earlier baicalein delivery systems built on Schiff-base chemistry, zeolitic imidazolate frameworks or chitosan, the dual-crosslinked supramolecular network offers superior mechanical strength and pH-tuned drug retention. The researchers caution that the findings rest on rodent models and that the Keap1/NRF2/HIF-1α mechanism, while strongly supported by knockdown, inhibitor and docking data, operates within a web of additional pathways including PI3K/Akt-mediated survival signaling. Even so, the strategy of targeting ferroptosis through a self-assembling, plant-inspired biomaterial offers a compelling template for the next generation of intelligent wound dressings, and it underscores how molecules refined by plant evolution over millions of years can be re-engineered, with the help of licorice nanofibers and a dash of zinc, into therapies for one of modern diabetes care’s most intractable problems.
Subject of Research: A supramolecular hydrogel delivering baicalein to inhibit ferroptosis and accelerate diabetic wound healing
Article Title: Bio-inspired supramolecular hydrogel inhibits ferroptosis to accelerate diabetic wound healing
Article References: Zou, H., Chen, J., Huang, Y., Li, J., Yuan, X., Chen, T., Ding, Y., Yang, P., Zheng, D., Chen, G., & Tan, Q. (2026). Bio-inspired supramolecular hydrogel inhibits ferroptosis to accelerate diabetic wound healing. Journal of Advanced Research, 88, 841-853. https://doi.org/10.1016/j.jare.2026.01.024
Image Credits: AI Generated
DOI: Not provided
Keywords: diabetic wounds, ferroptosis, baicalein, glycyrrhizic acid, hydrogel, NRF2, HIF-1α, GPX4, angiogenesis, zinc ions, wound dressing, nanofibers
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Ophelia Keating. (October 1, 2026). Plant-Powered Hydrogel Halts Cell Death to Heal Diabetic Wounds. Scienmag. https://scienmag.com/plant-powered-hydrogel-halts-cell-death-to-heal-diabetic-wounds/
Ophelia Keating. “Plant-Powered Hydrogel Halts Cell Death to Heal Diabetic Wounds.” Scienmag, 1 October 2026, https://scienmag.com/plant-powered-hydrogel-halts-cell-death-to-heal-diabetic-wounds/. Accessed 1 October 2026.
Ophelia Keating. “Plant-Powered Hydrogel Halts Cell Death to Heal Diabetic Wounds.” Scienmag. October 1, 2026. https://scienmag.com/plant-powered-hydrogel-halts-cell-death-to-heal-diabetic-wounds/
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Tags: angiogenesisbaicaleinbio-inspired supramolecular hydrogelschronic wound managementdiabetic wound healingdiabetic woundsendothelial cell protectionferroptosisferroptosis inhibitionglycyrrhizic acidGPX4HIF-1αhydrogelinnovative diabetic wound treatmentiron-driven cell deathnanofibersnatural flavonoid therapyNRF2oxidative stress in diabetic woundsplant-based hydrogel dressingstissue regeneration in diabeteswound dressingzinc ion incorporation in wound dressingszinc ions
