# Unravelling the pathophysiology of diabetic foot ulcer: insights into a complex wound healing process

**Authors:** Mohannad N. AbuHaweeleh, Sara Ali, Yasmin Elsalakawi, Aisha Al-Khulaifi, Viviana Maggio, Manfredi Rizzo, Ammar Boudaka

PMC · DOI: 10.3389/fcdhc.2026.1759605 · Frontiers in Clinical Diabetes and Healthcare · 2026-02-18

## TL;DR

This paper explores the complex healing process of diabetic foot ulcers to better understand and treat them.

## Contribution

The paper provides a comprehensive overview of the pathophysiological mechanisms underlying diabetic foot ulcers.

## Key findings

- DFU involves peripheral neuropathy, vascular insufficiency, and impaired immune response.
- Dysregulation in inflammation, angiogenesis, and extracellular matrix remodeling contributes to DFU.
- Understanding these mechanisms can lead to improved targeted therapies for DFU.

## Abstract

Diabetic foot ulcer (DFU) is a common and debilitating complication of diabetes mellitus, representing a significant clinical challenge. This article delves into the intricate pathophysiology underlying DFU, aiming to enhance our understanding of this complex wound healing process. We explore the interplay of multifactorial aspects, including peripheral neuropathy, vascular insufficiency, and impaired immune response, which contribute to the development and progression of DFU. Moreover, the dysregulation of key cellular and molecular mechanisms involved in inflammation, angiogenesis, extracellular matrix remodeling, and infection are examined. A comprehensive understanding of the pathophysiology of DFU including oxidative stress, neuropathy, dysregulated angiogenesis, impaired immune response, and key molecular pathways supports the development of targeted therapeutic strategies beyond current treatments to improve wound healing, reduce complications, and enhance patient quality of care.

## Linked entities

- **Diseases:** diabetes mellitus (MONDO:0005015)

## Full-text entities

- **Genes:** CCL5 (C-C motif chemokine ligand 5) [NCBI Gene 6352] {aka D17S136E, RANTES, SCYA5, SIS-delta, SISd, TCP228}, NOS3 (nitric oxide synthase 3) [NCBI Gene 4846] {aka EC-NOS, ECNOS, MYMY8, NOSIII, cNOS, eNOS}, IL4 (interleukin 4) [NCBI Gene 3565] {aka BCGF-1, BCGF1, BSF-1, BSF1, IL-4}, EGF (epidermal growth factor) [NCBI Gene 1950] {aka HOMG4, URG}, SERPINE1 (serpin family E member 1) [NCBI Gene 5054] {aka PAI, PAI-1, PAI1, PLANH1}, OGT (O-linked N-acetylglucosamine (GlcNAc) transferase) [NCBI Gene 8473] {aka HINCUT-1, HRNT1, MRX106, O-GLCNAC, OGT1, XLID106}, Prkcg (protein kinase C, gamma) [NCBI Gene 24681] {aka PKC, PKCI, Prkc, Prkcc, RATPKCI}, CXCL2 (C-X-C motif chemokine ligand 2) [NCBI Gene 2920] {aka CINC-2a, GRO2, GROb, MGSA-b, MIP-2a, MIP2}, IRS1 (insulin receptor substrate 1) [NCBI Gene 3667] {aka HIRS-1}, CALCA (calcitonin related polypeptide alpha) [NCBI Gene 796] {aka CALC1, CGRP, CGRP-I, CGRP-alpha, CGRP1, CT}, CD40LG (CD40 ligand) [NCBI Gene 959] {aka CD154, CD40L, HIGM1, IGM, IMD3, T-BAM}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, TAC1 (tachykinin precursor 1) [NCBI Gene 6863] {aka Hs.2563, NK2, NKNA, NPK, TAC2}, SORD (sorbitol dehydrogenase) [NCBI Gene 6652] {aka HEL-S-95n, HMNR8, RDH, SDH, SORD1, SORDD}, ICAM1 (intercellular adhesion molecule 1) [NCBI Gene 3383] {aka BB2, CD54, P3.58}, MMP2 (matrix metallopeptidase 2) [NCBI Gene 4313] {aka CLG4, CLG4A, MMP-2, MMP-II, MONA, TBE-1}, FGF7 (fibroblast growth factor 7) [NCBI Gene 2252] {aka HBGF-7, KGF}, RENBP (renin binding protein) [NCBI Gene 5973] {aka RBP, RNBP}, OLR1 (oxidized low density lipoprotein receptor 1) [NCBI Gene 4973] {aka CLEC8A, LOX1, LOXIN, SCARE1, SLOX1}, CASP3 (caspase 3) [NCBI Gene 836] {aka CPP32, CPP32B, SCA-1}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, IL12B (interleukin 12B) [NCBI Gene 3593] {aka CLMF, CLMF2, IL-12B, IMD28, IMD29, NKSF}, SELE (selectin E) [NCBI Gene 6401] {aka CD62E, ELAM, ELAM1, ESEL, LECAM2, selectin-e}, AKR1B1 (aldo-keto reductase family 1 member B) [NCBI Gene 231] {aka ADR, ALDR1, ALR2, AR}, CASP9 (caspase 9) [NCBI Gene 842] {aka APAF-3, APAF3, ICE-LAP6, MCH6, PPP1R56}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, ANXA5 (annexin A5) [NCBI Gene 308] {aka ANX5, CPB-I, ENX2, HEL-S-7, PP4, RPRGL3}, CD4 (CD4 molecule) [NCBI Gene 920] {aka CD4mut, IMD79, Leu-3, OKT4D, T4}, PROC (protein C, inactivator of coagulation factors Va and VIIIa) [NCBI Gene 5624] {aka APC, PC, PROC1, THPH3, THPH4}, CXCL8 (C-X-C motif chemokine ligand 8) [NCBI Gene 3576] {aka GCP-1, GCP1, IL8, LECT, LUCT, LYNAP}, PRRT2 (proline rich transmembrane protein 2) [NCBI Gene 112476] {aka BFIC2, BFIS2, DSPB3, DYT10, EKD1, FICCA}, Serpine1 (serpin family E member 1) [NCBI Gene 24617] {aka PAI1A, Pai1, Pai1aa, Planh, RATPAI1A}, IGF1 (insulin like growth factor 1) [NCBI Gene 3479] {aka IGF, IGF-I, IGFI, MGF}, SERPINC1 (serpin family C member 1) [NCBI Gene 462] {aka AT3, AT3D, ATIII, ATIII-R2, ATIII-T1, ATIII-T2}, SELP (selectin P) [NCBI Gene 6403] {aka CD62, CD62P, GMP140, GRMP, LECAM3, PADGEM}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, GFPT1 (glutamine--fructose-6-phosphate transaminase 1) [NCBI Gene 2673] {aka CMS12, CMSTA1, GFA, GFAT, GFAT 1, GFAT1}, CAT (catalase) [NCBI Gene 847], TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, FGF2 (fibroblast growth factor 2) [NCBI Gene 2247] {aka BFGF, FGF-2, FGFB, HBGF-2}, MPO (myeloperoxidase) [NCBI Gene 4353], CCL2 (C-C motif chemokine ligand 2) [NCBI Gene 6347] {aka GDCF-2, HC11, HSMCR30, MCAF, MCP-1, MCP1}, FAS (Fas cell surface death receptor) [NCBI Gene 355] {aka ALPS1A, APO-1, APT1, CD95, FAS1, FASTM}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, VCAM1 (vascular cell adhesion molecule 1) [NCBI Gene 7412] {aka CD106, INCAM-100}, F3 (coagulation factor III, tissue factor) [NCBI Gene 2152] {aka CD142, TF, TFA}, Vegfa (vascular endothelial growth factor A) [NCBI Gene 83785] {aka VEGF-A, VEGF111, VEGF164, VPF, Vegf}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, GSR (glutathione-disulfide reductase) [NCBI Gene 2936] {aka CNSHA10, GR, GSRD, HEL-75, HEL-S-122m}, MOK (MOK protein kinase) [NCBI Gene 5891] {aka RAGE, RAGE-1, RAGE1, STK30}, HK1 (hexokinase 1) [NCBI Gene 3098] {aka CNSHA5, HK, HK1-ta, HK1-tb, HK1-tc, HKD}, PF4 (platelet factor 4) [NCBI Gene 5196] {aka CXCL4, PF-4, SCYB4}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, FN1 (fibronectin 1) [NCBI Gene 2335] {aka CIG, ED-B, FINC, FN, FNZ, GFND}
- **Diseases:** autonomic (MESH:D001342), Hypoxia (MESH:D000860), post-injury inflammatory (MESH:D004834), autonomic neuropathy (MESH:D009422), necrosis (MESH:D009336), gangrene (MESH:D005734), neuronal dysfunction (MESH:D009461), dislocation (MESH:D004204), atheroma (MESH:D058226), Ischemia (MESH:D007511), neuronal injury and dysfunction (MESH:D006331), sensory loss (MESH:C580162), Hypercoagulability (MESH:D019851), peripheral neuropathies (MESH:D010523), Charcot foot (MESH:C564179), nephropathy (MESH:D007674), neuropathic (MESH:D009437), abnormal gait (MESH:D020233), cellulitis (MESH:D002481), deformity (MESH:D009140), neuronal damage (MESH:D009410), NETs (MESH:C536657), Insulin resistance (MESH:D007333), ulcer (MESH:D014456), bone destruction (MESH:D001847), Vascular insufficiency (MESH:D065666), loss of proprioception (MESH:D020886), foot deformities (MESH:D005530), diabetic retinopathy (MESH:D003930), DM (MESH:D003920), plaque rupture (MESH:D012421), infection (MESH:D007239), DN (MESH:D003929), atherogenesis (MESH:D050197), on mitochondrial function (MESH:D028361), Dyslipidemia (MESH:D050171), A myelinated (MESH:D003711), pain (MESH:D010146), blood maldistribution (MESH:D006402), metatarsal bone fractures (MESH:D050723), vascular impairments (MESH:D020141), hyperglycemic (MESH:D006944), Hyperglycemia (MESH:D006943), thrombosis (MESH:D013927), Charcot neuroarthropathy (MESH:D000690), fibrosis (MESH:D005355), loss of (MESH:D016388), T-cell (MESH:D016399), platelet aggregation (MESH:D001791), PVD (MESH:D016491), Microvascular dysfunction (MESH:D017566), Inflammation (MESH:D007249), blisters (MESH:D001768), Macrovascular disease (MESH:D004194), Wounds (MESH:D014947), DFU (MESH:D017719)
- **Chemicals:** ROS (MESH:D017382), FADH2 (MESH:C058805), hexosamine (MESH:D006595), nitric oxide (MESH:D009569), glucose (MESH:D005947), glutamate (MESH:D018698), DAG (MESH:D004075), NADH (MESH:D009243), STZ (MESH:D013311), lipid (MESH:D008055), Peroxynitrite (MESH:D030421), glutamine (MESH:D005973), GSH (MESH:D005978), AGEs (MESH:D017127), ATP (MESH:D000255), sorbitol (MESH:D013012), fructose (MESH:D005632), GlcNAc (MESH:D000117), fatty acids (MESH:D005227), Glucosamine-6-phosphate (MESH:C001293), ADP (MESH:D000244), TCA (MESH:D014238), glucose-6-phosphate (MESH:D019298), Polyol (MESH:C024617), oxygen (MESH:D010100), inorganic phosphate (MESH:D010710), Pi (MESH:D010716), proton (MESH:D011522), sugars (MESH:D000073893), fructose-6-phosphate (MESH:C027618), NO (MESH:D009614), uridine diphosphate N-acetylglucosamine (MESH:D014537), histamine (MESH:D006632), H2O2 (MESH:D006861), Advanced (-)
- **Species:** Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116]

## Full text

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## Figures

9 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12956518/full.md

## References

63 references — full list in the complete paper: https://tomesphere.com/paper/PMC12956518/full.md

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Source: https://tomesphere.com/paper/PMC12956518