From Honey to Healing Pathways: New Review Maps the Molecular Science of Wound Repair

Every cut, burn, and surgical incision sets off one of the most sophisticated repair programs in biology, and yet chronic wounds that refuse to heal remain a stubborn global health burden. A new integrative review published in Molecular Biology Reports by researchers at Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University in Karnataka, India, brings together two worlds that rarely meet in the same analysis: the dense molecular circuitry that governs skin repair, and the traditional and indigenous therapies that communities have used for centuries to treat injuries. The review, led by R. Dhanush and supervised by Bharathi Doddla Raghunathanaidu, synthesizes peer-reviewed evidence published between January 2005 and June 2026, drawing on searches of PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library, and applying SANRA guidelines for narrative reviews and the AMSTAR-2 checklist for the systematic reviews it cites.

The biological story at the heart of the review unfolds in four overlapping stages: hemostasis, inflammation, proliferation, and remodeling. Within seconds of injury, platelets aggregate and form a fibrin clot that stops blood loss and simultaneously releases an early burst of chemical signals. The review emphasizes that this initial clot is far more than a plug; it is a temporary scaffold soaked in platelet-derived growth factor and transforming growth factor beta, the molecules that recruit neutrophils and macrophages into the wound bed. Neutrophils arrive first, engulfing bacteria and releasing antimicrobial compounds, and recent work on neutrophil extracellular traps, web-like structures of DNA and toxic proteins that immobilize pathogens, illustrates how these cells shape the wound environment in ways that can either clear infection or, when excessive, damage surrounding tissue and prolong inflammation.

As inflammation gives way to proliferation, the cast of molecular players expands. The review catalogues the major growth factors and their receptors: vascular endothelial growth factor driving new blood vessel formation, epidermal growth factor and fibroblast growth factor stimulating keratinocyte and fibroblast division, and platelet-derived growth factor sustaining the migration of repair cells into the defect. These ligands feed into a remarkably interconnected web of intracellular signaling cascades, including SMAD, MAPK, PI3K/AKT, JAK/STAT, Wnt/beta-catenin, Notch, Hippo/YAP-TAZ, mTOR, and NF-kappaB pathways. The authors stress that no single pathway acts alone; transforming growth factor beta, for example, orchestrates both early inflammation and later scar formation through SMAD-dependent transcription, while hypoxia within the wound modifies how fibroblasts respond to its isoforms, linking oxygen tension directly to the quality of the matrix they deposit.

The extracellular matrix emerges in the review as far more than passive scaffolding. Collagen fibers, glycoproteins such as fibronectin and laminin, and bridging molecules like nidogen and perlecan form the basement membrane that underpins epidermal integrity, and their organization determines whether tissue regains strength or fails structurally. Specialized fibroblasts differentiate into myofibroblasts, the contractile cells that pull wound edges together, and their secretome interacts dynamically with the surrounding microenvironment. Single-cell RNA sequencing studies cited in the review reveal that fibroblasts in diabetic wounds are not a uniform population but a heterogeneous collection of subtypes, some of which appear locked into dysfunctional states. This heterogeneity helps explain why diabetic ulcers so often stall in a chronic, inflammatory phase and why therapies that work in acute wounds frequently disappoint in chronic ones.

Chronic wound biology occupies a central place in the analysis. In diabetes, persistently elevated pro-inflammatory cytokines disrupt the normal transition from the inflammatory to the proliferative phase, leaving wounds trapped in a self-perpetuating cycle of tissue destruction and incomplete repair. Microbial biofilms add another layer of complexity: structured bacterial communities encased in protective matrix resist both antibiotics and immune cells, and the review highlights recent work framing biofilms as major diagnostic and therapeutic barriers in non-healing wounds. Hypertrophic scarring and keloids represent the opposite failure mode, in which fibroblast activity and collagen deposition overshoot, producing raised, disfiguring lesions whose molecular pathogenesis, from altered growth factor signaling to mechanical tension, is now being mapped in detail. The review also notes the underappreciated symptom burden of chronic wounds, including the prevalence and mechanisms of itch, which affects quality of life in ways clinical metrics often overlook.

Against this molecular backdrop, the review turns to traditional and indigenous therapies, and this is where the narrative becomes genuinely striking. Honey, one of the oldest wound dressings known to medicine, receives the strongest evidential endorsement. A Cochrane systematic review on honey as a topical wound treatment, alongside more recent systematic reviews and meta-analyses of honey in diabetic foot ulcers, supports its antibacterial and healing-promoting properties, which are attributed to high osmolarity, acidity, hydrogen peroxide generation, and additional bioactive compounds. The authors point out that honey has effectively migrated from folk remedy to advanced wound care product, with medical-grade formulations now used in clinical settings worldwide.

Aloe vera is another traditional remedy with growing mechanistic support. Studies cited in the review show that aloe gel extracts promote fibroblast proliferation, migration, and viability, and that its phenolic and polysaccharide fractions contribute to wound-healing activity in vitro. The review also surveys a wide ethnobotanical landscape: Moringa oleifera fractions tested in human dermal fibroblasts, Vietnamese medicinal plants with documented traditional wound uses, Croton species from South American traditional medicine, Justicia pectoralis, prickly pear cactus, ash species from Caucasus ethnobotany, and neem oil, whose acute and subacute toxicity has been formally evaluated. Animal-derived remedies appear as well, including frog skin preparations and the antibacterial peptides discovered in frog skin secretions, such as dermaseptin-AC from the red-eyed tree frog Agalychnis callidryas, a molecule identified and rationally designed as a novel antimicrobial agent.

Perhaps the most vivid example of tradition validated by modern evidence is maggot debridement therapy, the controlled application of fly larvae to clean necrotic tissue from chronic wounds. A systematic review of maggot therapy in wound healing supports its role in removing dead tissue and controlling infection, and the review notes that some of these traditional treatments are now backed by Cochrane review-level evidence, the gold standard in evidence-based medicine. The authors also flag the ethical dimension of this research frontier: the Nagoya Protocol on access to genetic resources establishes the framework for fair and equitable benefit-sharing when indigenous knowledge and biological resources feed into commercial drug development, a reminder that translating traditional medicine into modern therapeutics carries obligations to the communities that preserved that knowledge.

The review situates these traditional approaches within the broader arc of modern wound care technology. Smart dressings that respond to the wound environment, collagen-based products, curcumin-loaded drug delivery systems for acute and chronic wounds, mesenchymal stem cell-derived exosomes, and bioengineered skin substitutes all feature in the cited literature as the field moves from passive coverage toward active, biology-directed intervention. Specialized pro-resolving lipid mediators and dietary omega-3 and omega-6 fatty acids represent another emerging strategy, aiming not to suppress inflammation but to actively resolve it, a concept that reframes chronic wounds as failures of resolution rather than simply failures of defense.

The authors’ conclusion is ultimately a call for integration. By connecting the molecular pathways that regulate each phase of repair, the cellular dysfunctions that trap wounds in chronicity, the newest biological therapies, and the evidence-based subset of traditional medicine, they argue, researchers can chart a path toward safer and more effective wound treatment. In an era when antimicrobial resistance threatens conventional approaches and diabetic wounds continue to consume enormous healthcare resources, the idea that a molecule from frog skin, a polysaccharide from aloe, or medical-grade honey might stand alongside growth factor therapeutics and engineered dressings is no longer fringe science. It is, the review suggests, exactly the kind of cross-disciplinary synthesis that chronic wound care has been waiting for, provided the evidence is gathered as rigorously as the molecular biology itself.

Subject of Research: The molecular mechanisms of skin wound healing and the evidence base for indigenous and traditional wound therapies

Article Title: An integrative review of wound healing: anatomy, molecular mediators, and indigenous therapies

Article References: Dhanush, R., Naveen, D. K., Sneha, H. R., Mudhol, S., & Raghunathanaidu, B. D. (2026). An integrative review of wound healing: anatomy, molecular mediators, and indigenous therapies. Molecular Biology Reports, 53(1), Article 1663. https://doi.org/10.1007/s11033-026-12835-2

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12835-2

Keywords: wound healing, growth factors, signaling pathways, chronic wounds, honey, Aloe vera, maggot debridement therapy, traditional medicine, indigenous therapies, extracellular matrix, biofilms, diabetic foot ulcers