Background: Hyperhomocysteinemia (HHcy) and type 2 diabetes (T2D) are recognized risk factors for non-healing wounds, yet their combined effects and underlying mechanisms remain unclear. Methods: In this study of 8406 National Health and Nutrition Examination Survey participants (1999–2004), weighted logistic regression was used to estimate odds ratios for non-healing wounds and Cox proportional hazards models were employed to assess hazard ratios for all-cause mortality. Additive and multiplicative interactions were evaluated. Nonlinear relationships used restricted cubic splines. Mediation analyses explored inflammatory marker contributions. Bulk transcriptomic and single-cell sequencing data were integrated to identify homocysteine (Hcy)-diabetic foot ulcers (DFU) hub genes, construct an Hcy risk gene scoring system, and elucidate key mechanisms by which Hcy remodels the DFU microenvironment. Results: Both T2D [odds ratio (OR): 2.42, 95% confidence interval (CI): 1.69–3.47] and HHcy (OR: 1.67, 95% CI: 1.10–2.54) independently elevated non-healing wound risk. Participants with both conditions exhibited higher odds (OR: 5.28, 95% CI: 3.20–8.70), with additive interaction (relative excess risk due to interaction: 2.83, AP: 0.54, SI: 2.95). In diabetic men, Hcy displayed a J-shaped relationship with non-healing wounds ( P for nonlinearity = 0.027), with the lowest risk around 8.9 µmol/L. In diabetic patients, inflammatory markers mediated the link, with proportions of 11.1% for red cell distribution width, 9.16% for monocyte/lymphocyte ratio, 5.28% for systemic inflammation response index, and 4.03% for neutrophil/lymphocyte ratio. Hcy drove immune-metabolic reprogramming in the DFU microenvironment by regulating key gene networks such as IL1B and MMP9, activating the MIF-CD74/CXCR4 axis to form a B cell-centric inflammatory cascade network. Both T2D and HHcy were associated with higher all-cause mortality, without joint interaction observed. Participants with a history of non-healing wounds had a higher all-cause mortality risk. Conclusions: T2D and HHcy synergistically worsen non-healing wounds, but not all-cause mortality. In diabetic males, Hcy levels displayed a J-shaped relationship with non-healing wound risk. Mechanistically, Hcy amplified systemic inflammation and drove stromal-immune crosstalk via the MIF-CD74/CXCR4 axis, reshaping the diabetic wound microenvironment.

Background: Condyloma acuminata (CA) is a common sexually transmitted disease caused by human papillomavirus (HPV). Abnormal keratinocyte proliferation is a hallmark of CA, but the underlying mechanisms remain unclear. BST2, an interferon-stimulated gene, is implicated in viral inhibition and tumor cell proliferation. This study aimed to investigate whether BST2 is involved in HPV-induced keratinocyte proliferation. Methods: We conducted bioinformatics analysis using publicly available datasets from the Gene Expression Omnibus (GEO) to assess BST2 expression in CA. HPV-6/11 live virus and HPV11-E7 lentiviruses were used to infect HaCaT cells to mimic early HPV infection and viral genome integration. We examined BST2 expression in both CA patient tissue samples and in vitro models using RT-qPCR, Western blot, and immunohistochemistry. To investigate the signaling mechanisms, we used siRNA to knock down key components of the cGAS/STING pathway and examined BST2 expression levels. Additionally, we assessed keratinocyte proliferation through CCK-8 assays and cell counting. Activation of downstream signaling pathways was evaluated using Western blot analysis for key molecules in the MEK/ERK/c-Myc pathway. Results: BST2 was significantly upregulated in CA lesions and HPV-infected keratinocytes through the cGAS/STING pathway. BST2 activation promoted keratinocyte proliferation via the MEK/ERK/c-Myc pathway, and this effect was significantly inhibited by BST2 knockdown. Conclusions: HPV could promote the proliferation of keratinocytes from condyloma acuminata lesions through inducing BST2, indicating that BST2 would be a potential therapeutic target for condyloma acuminata.