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Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Ferroptosis has been increasingly implicated in the pathophysiology of atrial fibrillation (AF). Pentoxifylline (PTX), a methylxanthine derivative, has shown potential therapeutic benefits in cardiovascular diseases; however, its unique role in ferroptosis-associated AF remains unclear. This study aimed to elucidate the molecular mechanisms through which PTX may exert therapeutic effects on ferroptosis-related AF, using a multifaceted approach integrating network pharmacology, bioinformatics, and experimental validation.Methods:Two transcriptomic datasets, GSE41177 and GSE79768, were retrieved from the Gene Expression Omnibus (GEO) to identify differentially expressed genes (DEGs) in AF. Ferroptosis-related genes (FRGs) were collected from the FerrDb database. PTX-associated targets were predicted using Super-PRED and SwissTargetPrediction. Overlapping DEGs and predicted PTX targets were intersected with FRGs to identify potential pharmacological targets. Candidate genes were further refined through protein-protein interaction (PPI) network construction and five topological algorithms (Degree, Maximum Neighborhood Component [MNC], Maximal Clique Centrality [MCC], Edge Percolated Component [EPC], and Closeness). Genes exhibiting consistent expression patterns in both GEO datasets were defined as key genes. Diagnostic value was assessed using receiver operating characteristic (ROC) curves. The immune infiltration landscape and correlations with key genes were analyzed via the CIBERSORT algorithm and Spearman correlation. Molecular docking was performed, and PyMOL was used to assess binding affinities between PTX and key gene-encoded proteins. In addition, regulatory networks involving non-coding RNAs and key genes were predicted. Single-cell RNA sequencing (scRNA-seq) was applied to determine cell-type\u2013specific gene expression. Finally, the therapeutic effects of PTX and the underlying ferroptosis-related molecular pathways were evaluated both in an acetylcholine (ACh)-CaCl2-induced AF rat model and in angiotensin II (AngII)-stimulated HL-1 cardiomyocytes.Results:From a total of 10,511 DEGs and 315 predicted PTX targets, 87 overlapping pharmacological targets were identified. Thirteen of these overlapped with known FRGs. Among them, PIK3CA and TLR4 emerged as key genes of interest based on PPI network centrality and consistent expression across datasets. Immune profiling revealed significant differences in six immune cell types between AF and control samples, with activated dendritic cells and follicular helper T cells negatively correlated with key gene expression. Molecular docking indicated favorable binding affinities between PTX and both PIK3CA (\u22124.33 kcal\/mol) and TLR4 (\u22123.72 kcal\/mol). Further analysis identified 23 microRNAs (miRNAs) predicted to target PIK3CA and TLR4, of which 21 miRNAs interacted with 22 long non-coding RNAs (lncRNAs), suggesting a complex regulatory network. scRNA-seq analysis revealed enriched PIK3CA expression in mast cells and elevated TLR4 expression in neutrophils and monocytes\/macrophages, suggesting involvement of immune-related mechanisms. In vivo, PTX significantly reduced AF susceptibility, shortened AF duration, and attenuated atrial structural remodeling. In AngII-stimulated HL-1 cardiomyocytes, PTX markedly suppressed intracellular Fe2+ accumulation. In both models, these protective effects coincided with downregulation of TLR4 and upregulation of PIK3CA, implicating modulation of ferroptosis-related pathways as the underlying mechanism.Conclusions:This study identifies PIK3CA and TLR4 as pivotal genes in the ferroptosis-associated molecular network of AF and as potential therapeutic targets of PTX. These findings support the potential of PTX to mitigate AF by regulating ferroptosis through these targets, providing a preclinical mechanistic basis for the potential value of PTX in AF management.<\/jats:p>","DOI":"10.31083\/fbl51871","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:17:49Z","timestamp":1785413869000},"source":"Crossref","is-referenced-by-count":0,"title":["The Ferroptosis-Related Mechanisms of Pentoxifylline in Atrial Fibrillation Treatment"],"prefix":"10.31083","volume":"31","author":[{"given":"Jia-Bin","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Cardiology, the Affiliated Wuxi People\u2019s Hospital of Nanjing Medical University, Wuxi People\u2019s Hospital, Wuxi Medical Center, Nanjing Medical University, 214023 Wuxi, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-Ye","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, the Affiliated Wuxi People\u2019s Hospital of Nanjing Medical University, Wuxi People\u2019s Hospital, Wuxi Medical Center, Nanjing Medical University, 214023 Wuxi, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cardiology, the Affiliated Wuxi People\u2019s Hospital of Nanjing Medical University, Wuxi People\u2019s Hospital, Wuxi Medical Center, Nanjing Medical University, 214023 Wuxi, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Peng","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Cardiology, the Affiliated Wuxi People\u2019s Hospital of Nanjing Medical University, Wuxi People\u2019s Hospital, Wuxi Medical Center, Nanjing Medical University, 214023 Wuxi, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Cardiology, the Affiliated Wuxi People\u2019s Hospital of Nanjing Medical University, Wuxi People\u2019s Hospital, Wuxi Medical Center, Nanjing Medical University, 214023 Wuxi, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-Hao","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Cardiology, the Affiliated Wuxi People\u2019s Hospital of Nanjing Medical University, Wuxi People\u2019s Hospital, Wuxi Medical Center, Nanjing Medical University, 214023 Wuxi, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan-Huan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, the Affiliated Wuxi People\u2019s Hospital of Nanjing Medical University, Wuxi People\u2019s Hospital, Wuxi Medical Center, Nanjing Medical University, 214023 Wuxi, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, the Affiliated Wuxi People\u2019s Hospital of Nanjing Medical University, Wuxi People\u2019s Hospital, Wuxi Medical Center, Nanjing Medical University, 214023 Wuxi, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Xian","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, the Affiliated Wuxi People\u2019s Hospital of Nanjing Medical University, Wuxi People\u2019s Hospital, Wuxi Medical Center, Nanjing Medical University, 214023 Wuxi, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, the Affiliated Wuxi People\u2019s Hospital of Nanjing Medical University, Wuxi People\u2019s Hospital, Wuxi Medical 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