Objective To construct a model of autophagy-related genes (ATGs) in the microcirculatory damage of extremities in patients with diabetic foot ulcers (DFU) based on bioinformatics analysis, and explore the related mechanisms and diagnostic/therapeutic targets. Methods Datasets GSE 134431, GSE 80178, and GSE 68183 were obtained from the GEO database, serving as training and validation sets, respectively. After data preprocessing, normalization, and batch correction, cluster analysis, GO and GSVA enrichment analysis, and WGCNA module identification were performed. Multiple machine learning methods were used to build prediction models, and performance was evaluated using nomograms, calibration curves, and decision curve analysis. Results A total of 20 differentially expressed genes were identified. Cluster analysis divided patients into 2 groups based on the presence or absence of microcirculatory damage. GO analysis revealed significant enrichment of genes in autophagosome-related structures, ubiquitin ligase binding, and cellular stress response processes. GSVA indicated significant enrichment in autophagy, mitophagy, and FoxO signaling pathways. The SVM model performed best (AUC=1.000), with an AUC of 0.929 in the validation set. Key genes included BNIP3, HEPHL1, and KLK10. Conclusions ATGs are involved in DFU microcirculatory damage by regulating mitophagy and the FoxO pathway. The SVM model demonstrates strong predictive ability, providing a basis for clinical diagnosis and targeted therapy.
Key words
Bioinformatics /
/
/
Autophagy-related genes /
/
/
Diabetic foot ulcers /
/
/
Microcirculatory damage at the extremity /
/
/
Model construction
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
References
[1] Armstrong DG, Tan TW, Boulton AJM, et al. Diabetic foot ulcers: A review[J]. JAMA, 2023, 330(1): 62-75. DOI:10.1001/jama.2023.10578
[2] Bolton L. Diabetic foot ulcer: treatment challenges[J]. Wounds, 2022, 34(6): 175-177. DOI:10.25270/wnds/2022.175177
[3] Pruthi S, Siddiqui E, Smilowitz NR. Beyond coronary artery disease: Assessing the microcirculation[J]. Interv Cardiol Clin, 2023, 12(1): 119-129. DOI:10.1016/j.iccl.2022.09.010
[4] Liu S, Yao S, Yang H, et al. Autophagy: Regulator of cell death[J]. Cell Death Dis, 2023, 14(10): 648-648. DOI:10.1038/s41419-023-06154-8
[5] Klionsky DJ, Petroni G, Amaravadi RK, et al. Autophagy in major human diseases[J]. EMBO J, 2021, 40(19): e108863. DOI:10.15252/embj.2021108863
[6] Cui K, Li Z. Identification and analysis of type 2 diabetes-mellitus-associated autophagy-related genes[J]. Front Endocrinol (Lausanne), 2023, 14(1): 1164112. DOI:10.3389/fendo.2023.1164112
[7] Wang L, Tian H, Wang H, et al. Disrupting circadian control of autophagy induces podocyte injury and proteinuria[J]. Kidney Int, 2024, 105(5): 1020-1034. DOI:10.1016/j.kint.2024.01.035
[8] Yang YY, Gao ZX, Mao ZH, et al. Identification of ULK1 as a novel mitophagy-related gene in diabetic nephropathy[J]. Front Endocrinol (Lausanne), 2023, 13(1): 1079465. DOI:10.3389/fendo.2022.1079465
[9] Ramirez HA, Pastar I, Jozic I, et al. Staphylococcus aureus triggers induction of miR-15B-5P to diminish DNA repair and deregulate infammatory response in diabetic foot ulcers[J]. J Invest Dermatol, 2018, 138(5): 1187-1196. DOI:10.1016/j.jid.2017.11.038
[10]Sawaya AP, Stone RC, Brooks SR, et al. Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing[J]. Nat Commun, 2020, 11(1): 4678. DOI:10.1038/s41467-020-18276-0
[11]Stone A, Donohue CM. Diabetic foot ulcers in geriatric patients[J]. Clin Geriatr Med, 2024, 40(3): 437-447. DOI:10.1016/j.cger.2024.03.002
[12]Aldana PC, Cartron AM, Khachemoune A. Reappraising diabetic foot ulcers: A focus on mechanisms of ulceration and clinical evaluation[J]. Int J Low Extrem Wounds, 2022, 21(3): 294-302. DOI:10.1177/15347 34620944514
[13]Falhammar H. Diabetic foot ulcers - The time to act is now[J]. Indian J Med Res, 2022, 156(4&5): 570-572. DOI: 10.4103/ijmr.ijmr_2116_22
[14]Jeffcoate W, Boyko EJ, Game F, et al. Causes, prevention, and management of diabetes-related foot ulcers. Lancet Diabetes Endocrinol. 2024, 12(7): 472-482. DOI:10.1016/S2213-8587(24)00110-4
[15]韩志芬, 康彧, 王渠, 等. 超声造影在评价糖尿病足溃疡患者肢端微循环损害中的应用价值[J]. 中国超声医学杂志, 2023, 39(5): 573-576. DOI:10.3969/j.issn.1002-0101.2023.05.028.
Han ZF, Kang Y, Wang Q, et al. Application Value of Ultrasound Contrast in Evaluating Microcirculatory Impairment in Diabetic Foot Ulcer Patients [J]. Chinese Journal of Ultrasound in Medicine, 2023, 39(5): 573-576. DOI:10.3969/j.issn.1002-0101.2023.05.028.
[16]Salemkour Y, Lenoir O. Endothelial autophagy dysregulation in diabetes[J]. Cells. 2023, 12(6): 947. DOI:10.3390/cells12060947
[17]Ou Y, Zhao YL, Su H. Pancreatic β-Cells, diabetes and autophagy[J]. Endocr Res, 2025, 50(1): 12-27. DOI:10.1080/07435800.2024.2413064
[18]Arden C, Park SH, Yasasilka XR, et al. Autophagy and lysosomal dysfunction in diabetes and its complications[J]. Trends Endocrinol Metab, 2024, 35(12): 1078-1090. DOI:10.1016/j.tem.2024.06.010
[19]Li X, Luo W, Tang Y, et al. Semaglutide attenuates doxorubicin-induced cardiotoxicity by ameliorating BNIP3-Mediated mitochondrial dysfunction[J]. Redox Biol, 2024, 72(1): 103129. DOI:10.1016/j.redox. 2024.103129
[20]Yang C, Yi B, Yang S, et al. VDR restores the expression of PINK1 and BNIP3 in TECs of streptozotocin-induced diabetic mice[J]. Life Sci Alliance, 2024, 7(7): e202302474. DOI:10.26508/lsa.202302474
[21]Gil J, Marques-Pamies M, Valassi E, et al. Molecular characterization of epithelial-mesenchymal transition and medical treatment related-genes in non-functioning pituitary neuroendocrine tumors[J]. Front Endocrinol (Lausanne), 2023, 14(1):1129213. DOI:10.3389/fendo.2023. 1129213
[22]Williams D, Mahmoud M, Liu R,et al. Stable flow-induced expression of KLK10 inhibits endothelial inflammation and atherosclerosis[J]. Elife, 2022, 11(1):e72579. DOI:10.7554/eLife.72579
[23] Oh SJ, Lee MS. Role of autophagy in the pathogenesis of diabetes and therapeutic potential of autophagy modulators in the treatment of diabetes and metabolic syndrome[J]. J Korean Med Sci, 2022, 37(37): e276. DOI:10.3346/jkms.2022.37.e276
[24]Shan Z, Fa WH, Tian CR, et al. Mitophagy and mitochondrial dynamics in type 2 diabetes mellitus treatment[J]. Aging (Albany NY), 2022, 4(6): 2902-2919. DOI:10.18632/aging.203969
[25]Chen D, Chen X, He C, et al. Sanhuang xiexin decoction synergizes insulin/PI3K-Akt/FoxO signaling pathway to inhibit hepatic glucose production and alleviate T2DM[J]. J Ethnopharmacol, 2023, 306(1): 116162. DOI:10.1016/j.jep.2023.116162
[26]Cui K, Li Z. Identification and analysis of type 2 diabetes-mellitus-associated autophagy-related genes[J]. Front Endocrinol (Lausanne), 2023, 14(1): 1164112. DOI:10.3389/fendo.2023.1164112
PDF(4326 KB)
