Ferroptosis Emerges as a Critical Player in Diabetic Wound Repair: New Avenues for Therapeutic Innovation
Diabetic wounds, notorious for their stubborn resistance to healing, represent a multifaceted clinical challenge involving disrupted cellular responses and chronic inflammation. Recent scientific explorations have spotlighted a novel form of regulated cell death known as ferroptosis, which appears integral to the impaired repair mechanisms underpinning these wounds. Unlike traditional modes of cell death characterized by apoptosis or necrosis, ferroptosis is driven by iron-dependent accumulation of lipid peroxides, unveiling a fresh dimension in understanding diabetic wound pathophysiology and unveiling promising therapeutic targets.
The wound-healing process intricately involves a symphony of cell types—macrophages, fibroblasts, endothelial cells, and keratinocytes—all of which demonstrate dysfunction under diabetic conditions aggravated by oxidative stress and reactive oxygen species (ROS) surges. These cellular derangements precipitate ferroptotic cascades, profoundly impairing tissue regeneration. Emerging evidence suggests that modulating ferroptosis may hold the key to tipping the scales toward effective healing in diabetes-compromised tissue microenvironments.
Macrophages are central architects of inflammation regulation and tissue restoration, orchestrating debris clearance and cytokine secretion vital for extracellular matrix (ECM) remodeling. In diabetic wounds, ferroptosis disrupts macrophage polarization—the dynamic shift between pro-inflammatory (M1) and reparative (M2) phenotypes. Iron homeostasis intricately influences this polarization; optimal iron promotes M2 states, fostering healing through secretion of ECM-enhancing cytokines like CCL17 and CCL22. However, iron overload skews macrophages toward M1 polarization by amplifying ROS production and activity of acetylated p53 transcription factors, fueling persistent inflammation. Remarkably, inhibitors such as Ferrostatin-1 attenuate ferroptosis in macrophages, reducing inflammation and facilitating angiogenesis, partly mediated by upregulating nuclear factor-E2-related factor 2 (Nrf2), a master regulator of antioxidant defenses.
Fibroblasts, the principal architects of ECM synthesis and scar tissue formation, are not spared from ferroptosis’s detrimental influence. Under oxygen and glucose deprivation, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy fosters ferroptosis in dermal fibroblasts, delaying ischemic wound healing. Diabetic hyperglycemia exacerbates fibroblast dysfunction by activating ferroptotic pathways, impairing cellular survival, proliferation, and migration. Interventions targeting ferroptosis, such as the application of Ferrostatin-1 or platelet-rich plasma (PRP), have demonstrated restoration of fibroblast functionality and activation of pro-survival signaling cascades like phosphatidylinositol 3-kinase (PI3K)/AKT. Moreover, the novel approach of delivering secretory autophagosomes from endothelial cells to fibroblasts modulates iron overload and oxidative stress—reversing ferroptosis and enhancing wound closure. Intriguingly, senescent fibroblasts in diabetic wounds exhibit ferroptosis resistance due to impaired ferritinophagy, but enhancing NCOA4 expression reverses this trait, suggesting a complex interplay between cellular aging and ferroptotic susceptibility.
Endothelial cells, pivotal for neovascularization and vascular integrity, confront significant ferroptotic stress in diabetic milieus marked by reduced capillary density and impaired angiogenesis. High-glucose exposure detrimentally affects proliferation, migration, and barrier function of endothelial cells, with ferroptosis emerging as a key mediator. Ferrostatin-1 rescues endothelial cells by downregulating ferroptosis-related proteins, mitigating lipid peroxidation and ROS accumulation. PRP also conveys protective effects by diminishing ferroptosis, thus fostering regeneration. At the molecular level, Nrf2 orchestrates a defensive response by regulating genes like glutathione peroxidase 4 (GPX4) and glucose-6-phosphate dehydrogenase (G6PD), essential for counteracting oxidative damage. Activation of transient receptor potential ankyrin 1 (TRPA1) channels triggers Ca²⁺ influx and subsequent Nrf2 nuclear translocation, mechanistically suppressing ferroptosis and enhancing angiogenic potential. Additionally, natural compounds such as resveratrol and synthetic metabolites like 4-octyl itaconate bolster Nrf2 signaling, alleviating ferroptosis in endothelial cells and promoting wound repair. Notably, immune cell interactions, specifically neutrophil extracellular traps (NETs), may exacerbate endothelial ferroptosis by inhibiting PI3K/AKT pathways, further compromising wound vascularization.
Keratinocytes, the frontline defenders forming the epidermal barrier, also succumb to ferroptotic insults in diabetic wounds. Advanced glycation end products (AGEs) accumulate in diabetes, provoking oxidative stress and lipid peroxidation that induce keratinocyte ferroptosis. The autophagy-lysosome pathway, crucial for degrading pro-ferroptotic enzymes such as acyl-CoA synthetase long-chain family member 4 (ACSL4), is impaired due to reduced expression of sequestosome 1 (SQSTM1), further sensitizing keratinocytes to ferroptotic death. Cutting-edge studies have revealed that exosomes derived from coenzyme Q10-treated mesenchymal stem cells (MSCs) transport microRNAs that suppress ACSL4 expression, protect keratinocytes, and accelerate re-epithelialization. Despite the complexity, targeting keratinocyte ferroptosis represents a fertile area for therapeutic development in diabetic wound management.
Beyond mammalian cells, bacterial pathogens in diabetic wounds present a significant challenge due to infection susceptibility and altered host defenses. Traditional antimicrobial approaches face limitations, prompting innovative strategies that exploit ferroptosis-like mechanisms to target bacteria. While many bacterial membranes lack polyunsaturated fatty acids (PUFAs) vulnerable to ferroptotic lipid peroxidation, some species can synthesize or integrate PUFAs, rendering them susceptible to ferroptosis-inducing agents. Recent advances include engineered nanomaterials and bio-heterojunctions designed to deliver iron ions directly to bacterial cells, triggering lipid peroxidation and ferroptosis-like death without harming host tissues. For instance, the creation of bio-heterojunctions combining Fe₂O₃, Ti₃C₂-MXene, and glucose oxidase effectively starves bacteria by depleting glucose, promoting targeted ferroptosis, while simultaneously protecting macrophages from oxidative damage. Similarly, microneedle hydrogels loaded with iron-based nanomaterials selectively induce intracellular reactive oxygen species in bacteria, demonstrating potent antimicrobial and wound-healing effects. Such approaches signify a paradigm shift in infected diabetic wound therapy.
The coordinated modulation of ferroptosis across diverse cellular players in the diabetic wound microenvironment highlights its role as a common denominator in pathological remodeling and repair failure. Therapeutic strategies harnessing ferroptosis inhibitors, activators, and nanotechnologies hold promise for simultaneously ameliorating chronic inflammation, restoring cellular vitality, and enhancing microbial clearance. Central to these advances is the transcription factor Nrf2, whose regulatory axis spans antioxidant response, iron metabolism, and ferroptosis suppression, making it a strategic target for pharmacological intervention.
Future research is poised to unravel the nuanced crosstalk between ferroptosis and other forms of regulated cell death in diabetic wounds, with implications extending to fibrosis, angiogenesis, and immune surveillance. Moreover, exploring the interplay between cellular senescence, autophagy dysregulation, and ferroptosis resistance could yield transformative insights into chronic wound recalcitrance. The integration of bioengineering and nanomedicine offers exciting venues for precision delivery of ferroptosis modulators, enhancing safety and efficacy.
In closing, the burgeoning field of ferroptosis research redefines our understanding of diabetic wound pathology and treatment. By decoding the iron-dependent, lipid peroxidation-driven mechanisms that disrupt multiple cell types—macrophages, fibroblasts, endothelial cells, keratinocytes—and employing innovative ferroptosis-targeting therapies against both host and bacterial cells, we edge closer to resolving a pervasive medical challenge. This pioneering science not only illuminates fundamental biological processes but also ushers in a new era of therapeutic possibilities for diabetic patients worldwide.
Subject of Research: The role and mechanisms of ferroptosis in the repair and healing of diabetic wounds.
Article Title: Research progress on the role and mechanisms of ferroptosis in diabetic wound repair.
Article References:
Zhang, W., He, H., Chen, S. et al. Research progress on the role and mechanisms of ferroptosis in diabetic wound repair. Cell Death Discov. 11, 515 (2025). https://doi.org/10.1038/s41420-025-02808-y
Image Credits: AI Generated
DOI: 10.1038/s41420-025-02808-y
Keywords: Ferroptosis, diabetic wounds, macrophages, fibroblasts, endothelial cells, keratinocytes, iron homeostasis, lipid peroxidation, Nrf2, oxidative stress, wound healing, antimicrobial therapy, nanomedicine
Tags: cellular responses in diabetic woundsdiabetic tissue microenvironmentsdiabetic wound repair challengesECM remodeling in diabetic woundsferroptosis in diabetic wound healinginflammation regulation in diabetesiron-dependent cell death mechanismslipid peroxides in cell deathmacrophage function in wound healingmechanisms of ferroptosisoxidative stress and wound healingtherapeutic innovations for diabetic wounds
