Iron is required for oxygen transport, mitochondrial respiration, DNA synthesis and numerous enzymatic reactions. Systemic iron homeostasis depends on intestinal absorption, transferrin-mediated transport, transferrin receptor-dependent uptake, ferritin storage, ferroportin-mediated export and macrophage recycling of senescent erythrocytes. During normal repair, adequate iron supports cell proliferation, host defense and collagen synthesis. In diabetic wounds, however, persistent inflammation and oxidative stress can disturb hepcidin, ferroportin, transferrin receptor and ferritin expression, thereby enlarging the local labile iron pool [8][9]. Excess ferrous iron promotes Fenton chemistry and generates hydroxyl radicals that attack polyunsaturated phospholipids. Iron is therefore a genuine double-edged factor. Indiscriminate chelation could compromise proliferative and antimicrobial functions, whereas uncontrolled iron accumulation amplifies oxidative injury and sensitizes reparative cells to ferroptosis. A rational treatment should reduce the redox-active iron pool without depriving regenerating tissue of iron required for metabolism and matrix formation.

Lipid peroxidation is the execution phase of ferroptosis. Membrane phospholipids containing arachidonic or adrenic acid can be oxidized through enzymatic and non-enzymatic reactions. If phospholipid hydroperoxides are not reduced, membrane fluidity declines, permeability rises and organelle function deteriorates. Autophagic degradation, mitochondrial injury, endoplasmic reticulum stress and antioxidant capacity together determine whether an oxidative challenge remains reversible or progresses to ferroptotic death [10][11]. The SLC7A11-GSH-GPX4 pathway is the best-characterized anti-ferroptotic system. SLC7A11 is the light-chain component of system Xc−, the cystine/glutamate antiporter. Imported cystine is reduced to cysteine and used for glutathione (GSH) synthesis. Glutathione peroxidase 4 (GPX4) then uses GSH to reduce phospholipid hydroperoxides to less reactive lipid alcohols. Reduced SLC7A11 expression, GSH depletion or GPX4 inhibition permits accumulation of lipid ROS, MDA and 4-HNE and lowers the threshold for ferroptosis [12][13].

A GPX4-centered model is incomplete. Ferroptosis suppressor protein 1 (FSP1) regenerates reduced coenzyme Q10 at the plasma membrane and can inhibit lipid peroxidation independently of GSH and GPX4. In mitochondria, dihydroorotate dehydrogenase (DHODH) supports a parallel CoQ-dependent defense, whereas GTP cyclohydrolase 1 (GCH1) and tetrahydrobiopterin (BH4) protect selected phospholipid pools through radical-trapping and lipid-remodeling effects [14]-[16]. These backup systems are well established in general ferroptosis biology but have received little direct study in diabetic wounds. This gap has two implications. First, restoration of GPX4 alone may not explain the full response to a treatment. Second, cells that retain FSP1-, DHODH- or BH4-dependent protection may appear resistant despite substantial oxidative stress. Future wound studies should therefore measure more than the canonical SLC7A11-GSH-GPX4 axis and determine whether the relevant defense pathway differs among keratinocytes, fibroblasts, macrophages and endothelial cells.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a central transcriptional regulator of antioxidant and iron-handling responses. Under basal conditions, NRF2 is restrained mainly by Kelch-like ECH-associated protein 1 (KEAP1)-dependent degradation. Oxidative or electrophilic stress stabilizes NRF2, allowing it to induce HMOX1, NQO1, GCLC, SLC7A11 and GPX4. SLC7A11 also intersects with immune regulation, insulin secretion, mTOR signaling and cellular redox balance [17]-[19]. Experimental diabetic wound models support the relevance of this axis. Early work identified ferroptotic features in diabetic wounds and showed that ferroptosis inhibition reduced inflammatory injury. Bone marrow stromal cell-derived exosomal circular RNA and an MMP-9-responsive cinnamaldehyde hydrogel have subsequently been reported to activate NRF2-related anti-ferroptotic signaling and improve angiogenic repair [20]-[22]. Macrophage and endothelial studies further connect NRF2 with inflammatory resolution and neovascularization. Ferrostatin-1 reduced high-glucose-induced macrophage injury through NRF2 activation, whereas mesenchymal stromal cell-derived extracellular vesicles inhibited neutrophil extracellular trap (NET)-induced endothelial ferroptosis and improved vessel formation [23][24]. Energy-sensing pathways add another layer of context. Meteorin-like protein attenuated mitochondrial damage and ferroptosis through LKB1/AMPK-related signaling in a diabetic foot ulcer model. In contrast, AMPK activation can promote NCOA4-mediated ferritinophagy and facilitate clearance of senescent cells. AMPK therefore cannot be assigned a uniformly anti- or pro-ferroptotic role; its effect depends on cell identity, metabolic state and wound stage [25][26] (Figure 1).

Hyperglycemia, ischemia, infection and persistent inflammation promote iron dysregulation, mitochondrial/endoplasmic reticulum stress and failure of antioxidant defenses. Lipid peroxidation then impairs macrophage state transitions, re-epithelialization, matrix formation and angiogenesis. Therapeutic direction should be determined by cell identity and wound stage: reparative cells generally require protection, whereas selective elimination of defined pathological cell states remains an experimental strategy. BH4, tetrahydrobiopterin; DHODH, dihydroorotate dehydrogenase; ER, endoplasmic reticulum; FSP1, ferroptosis suppressor protein 1; NETs, neutrophil extracellular traps; PUFA, polyunsaturated fatty acid.

Macrophages coordinate the transition from inflammation to tissue repair. The commonly used M1/M2 terminology is a simplification—wound macrophages occupy a continuum of activation states—but it remains useful for describing the failure of diabetic wounds to move from inflammatory to reparative programs. Persistent inflammatory macrophage states are associated with weak efferocytosis,

Figure 1.Cell- and stage-specific framework linking the diabetic wound microenvironment to ferroptosis and therapeutic direction.

sustained cytokine release and impaired angiogenic and matrix-remodeling support. Iron handling is closely linked to macrophage function, and tissue iron can promote reparative polarization and chemokine programs involved in re-epithelialization [27][28]. The therapeutic implication is not that all macrophage ferroptosis should be suppressed. In hyperglycemic or infected wounds, iron overload and lipid peroxidation can injure macrophages and prolong inflammation, making ferroptosis inhibition beneficial. Conversely, experimental systems that induce ferroptosis in selected inflammatory macrophage populations have reduced inflammatory burden. Work involving asiaticoside-loaded GelMA and the NINJ1-STAT3 axis illustrates this bidirectionality, but the evidence remains preclinical and does not justify indiscriminate macrophage depletion [29][30].

Evidence source and causal interpretation. The direct diabetic-wound evidence supporting macrophage ferroptosis is derived from cultured macrophages and diabetic rodent wound models rather than from cell-resolved human DFU intervention studies. The asiaticoside/GelMA and NINJ1 studies used ferroptosis-directed mechanistic perturbation and are therefore interpreted as ferroptosis-causal at the preclinical level [29][30]. Iron-handling and macrophage-polarization observations without ferroptosis-specific rescue are interpreted as oxidative-injury-associated rather than proof of ferroptotic death [28].

Keratinocytes restore the epidermal barrier through proliferation, migration and differentiation. High glucose and advanced glycation end products increase Fe²⁺, ROS and MDA while reducing GPX4 and ferritin expression. Berberine has been reported to activate NRF2 and restore anti-ferroptotic proteins in diabetic skin. More recent studies implicate histone lysine crotonylation, SQSTM1/p62-dependent autophagy, YTHDF2-mediated m6A regulation and ACSL4-dependent lipid remodeling. Keratinocyte ferroptosis is therefore not simply a passive consequence of oxidative stress; it is embedded in epigenetic, post-transcriptional and autophagic control of lipid metabolism [31]-[33].

Evidence source and causal interpretation. The cited evidence consists principally of keratinocyte cultures and diabetic mouse or rat wound models; no study cited here establishes keratinocyte ferroptosis causally in human DFU tissue. Berberine-associated changes in Fe²⁺, ROS/MDA and NRF2/GPX4 are treated as oxidative-injury-associated/ferroptosis-supportive [31], whereas ACSL4/YTHDF2 pathway perturbation and ferroptosis-inhibitor rescue in the mechanistic studies meet the review’s ferroptosis-causal criterion at the preclinical level [32][33].

Fibroblasts synthesize collagen, organize extracellular matrix and determine the mechanical quality of granulation tissue. High glucose reduces fibroblast proliferation, migration and collagen secretion while increasing Fe²⁺, ROS and MDA. Beta-boswellic acid has been reported to inhibit STAT3-associated fibroblast ferroptosis and improve collagen deposition in diabetic rats. Platelet-rich plasma-derived exosome hydrogels can restore GPX4/SLC7A11 expression, whereas NETs induce fibroblast ferroptosis through IRE1α/XBP1-mediated endoplasmic reticulum stress and suppress collagen production. These observations place neutrophil-fibroblast and platelet/exosome-fibroblast crosstalk at the center of granulation-tissue failure [34]-[36].

Evidence source and causal interpretation. These conclusions derive from fibroblast cell culture, including human skin fibroblast preparations, together with streptozotocin-diabetic rodent wound models rather than a clinical fibroblast intervention study. The beta-boswellic-acid study combined human skin fibroblast experiments with a diabetic rat model and showed ferrostatin-1-sensitive effects, supporting a preclinical ferroptosis-causal interpretation [34]. NET/IRE1α-XBP1 and PRP-exosome experiments are classified as ferroptosis-causal only where pathway perturbation or ferroptosis-directed rescue accompanies lipid-peroxidation readouts; marker-only changes remain oxidative-injury-associated [35][36].

Endothelial dysfunction contributes to hypoxia, poor microcirculatory perfusion and weak angiogenesis in diabetic wounds. High glucose damages mitochondria, raises ROS and promotes phospholipid peroxidation, reducing endothelial proliferation, migration and tube formation. Adipose stem cell-derived apoptotic vesicles can suppress endothelial ferroptosis and improve angiogenesis. The cGAS-STING pathway and CEBPD-dependent CXCL10 transcription have also been linked to Fe²⁺ accumulation, GPX4 loss and impaired tissue regeneration. Endothelial ferroptosis therefore affects both vessel growth and the inflammatory tone of the wound bed [37]-[39].

Evidence source and causal interpretation. The available data are predominantly endothelial-cell culture and diabetic rodent wound studies. Apoptotic-vesicle and cGAS-STING studies include mechanistic perturbation or rescue and are treated as preclinical ferroptosis-causal evidence [37][38]. CEBPD-CXCL10 findings are interpreted as ferroptosis-causal only to the extent that pathway manipulation is linked to Fe²⁺/GPX4 and functional wound-repair changes; marker associations alone remain oxidative-injury-associated [39]. No cell-resolved human DFU study cited here establishes endothelial ferroptosis causally.

Table 1 summarizes the experimental source, causal grade and therapeutic interpretation for the principal cell-specific evidence.

Table 1.Cell-specific evidence, causal classification and therapeutic implications of ferroptosis in diabetic wound repair.

Natural compounds are attractive because many combine antioxidant, anti-inflammatory and pro-angiogenic activity. Hesperetin activates SIRT3 and limits lipid peroxidation, while orientin stimulates NRF2/GPX4 signaling. Dulaglutide, a glucagon-like peptide-1 receptor agonist, restored NRF2, GPX4 and SLC7A11 signaling and reduced keratinocyte ferroptosis in diabetic mice. These studies provide mechanistic leads, but most use a single rodent model and do not compare the candidate treatment with contemporary wound-care standards [42]-[44].

Traditional formulations have also generated mechanistic data. Ruan Jian Qing Mai formula attenuated NINJ1-associated macrophage ferroptosis, whereas Chuangling Ye suppressed keratinocyte ferroptosis by inhibiting ACSS2-mediated ACSL4 acetylation. These findings are more informative than generic pathway-enrichment analyses because they include functional validation. Even so, translation requires batch-level chemical characterization, identification of active constituents, dose-response relationships, pharmacodynamic markers and reproducible local-safety assessment [45].

Extracellular vesicles can transport microRNAs, circular RNAs, proteins and mitochondrial components and thereby modify inflammation, angiogenesis and redox metabolism. Bone marrow mesenchymal stromal cell-derived exosomes carrying circ-Snhg11 enhanced SLC7A11/GPX4-dependent protection. Platelet-rich plasma (PRP) has likewise been associated with reduced oxidative and ferroptotic markers and improved healing in diabetic ulcer models. The main obstacle is standardization: vesicle isolation, potency assays, storage, PRP platelet concentration, leukocyte content, activation method and dosing schedule vary substantially across studies [46]-[48].

Diabetic wounds commonly contain bacterial biofilms and drug-resistant organisms, but clinical healing is also strongly influenced by devitalized tissue, peripheral artery disease/ischemia and repetitive pressure loading. Contemporary DFU management therefore relies on infection assessment and appropriately targeted antimicrobial therapy, debridement when indicated, vascular assessment and revascularization when needed, pressure offloading, and evidence-based wound-healing care. Ferroptosis-directed materials should be evaluated as adjuncts to, rather than substitutes for, these standards [49]-[53]. Nanomaterials and hydrogels can improve local retention, provide controlled release, maintain a moist environment and combine antimicrobial and regenerative functions. Prussian blue analogue nanozymes have been designed to reduce Fe²⁺ accumulation and lipid peroxidation while promoting a reparative macrophage phenotype. Ferrous sulfide/glycyrrhizic acid hydrogels can modify ROS and inflammatory conditions in infected diabetic wounds [54][55]. Newer systems attempt to protect host reparative cells while producing oxidative membrane injury in bacteria. Fe₃O₄/MXene heterojunction GelMA microneedles and defect-engineered Fe-WS2@glucose oxidase nanozymes illustrate this approach. Because bacteria lack the canonical mammalian ferroptosis machinery, “ferroptosis-like bacterial death” is the more defensible term. Long-term material retention, degradation products, immunogenicity, activation parameters and batch-to-batch reproducibility remain unresolved [40][41].

Table 2 compares the translational readiness of the major intervention classes against these clinical-development requirements.

Table 2.Translational readiness of major ferroptosis-targeted intervention classes.