{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T18:24:49Z","timestamp":1787855089374,"version":"build-2784847793"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T00:00:00Z","timestamp":1752451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Autophagy induced by itraconazole and ritonavir was found involved in the pathogenesis of <jats:italic>C. albicans<\/jats:italic>. This study was designed to explore the possible molecular mechanism of itraconazole and ritonavir in the treatment of <jats:italic>Candida albicans<\/jats:italic> infection through autophagy pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The overlapping targets of itraconazole and ritonavir, and those-related to <jats:italic>C. albicans<\/jats:italic> and autophagy were screened. Then the core targets were identified by protein-protein interaction (PPI) network analysis. Gene enrichment analysis of targets and the drug-target-pathway-disease network was constructed. The interactions between itraconazole, ritonavir and core targets were analyzed by molecular docking and molecular dynamics simulation. Finally, the core target-miRNA interaction network was constructed to predict candidate miRNAs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PPI network showed that PIK3R1, RELA, STAT3, HSP90AA1, TP53, JUN, GRB2, EGFR, ESR1 and TNF were potential core targets of autophagy therapy for <jats:italic>C. albicans<\/jats:italic> infection with itraconazole and ritonavir. Enrichment analysis showed that the two drugs may regulate the autophagy process through pathways including PI3K-AKT, IL-17, MAPK, Toll-like receptor, JAK-STAT and NF-\u03baB. Molecular docking analysis indicated that itraconazole and ritonavir possess strong binding affinities with the cote target proteins, with binding free energies ranging from \u22125.6 to \u22129.5\u00a0kcal\/mol. Key interactions were identified at the active sites of the targets, suggesting stable ligand-receptor complex formation. Itraconazole docked to PIK3R1 through SER-78 and GLU-82 (\u22129.3\u00a0kcal\/mol), and ritonavir docked to PIK3R1 through ASN-85, GLU-1011 and arginine (ARG)-1088 (\u22127.7\u00a0kcal\/mol). Molecular dynamics simulation of itraconazole and ritonavir with representative target genes lasted for 100\u00a0ns showed the structures of the formed complexes remained stable throughout. Finally, the candidate miRNAs including miR-486-5p, miR-411-5p.1 and miR-296-5p were identified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Network pharmacological analysis showed a multi-target and multi-pathway molecular mechanism of itraconazole and ritonavir in the treatment of <jats:italic>C. albicans<\/jats:italic> infection, and provided a theoretical basis for subsequent studies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1578749","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T05:25:52Z","timestamp":1752470752000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Exploring the therapeutic mechanism of itraconazole combined with ritonavir on Candida albicans infection through network pharmacology and molecular docking"],"prefix":"10.3389","volume":"16","author":[{"given":"Yiyang","family":"Feng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenli","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"B2","doi-asserted-by":"publisher","first-page":"468","DOI":"10.3390\/jof9040468","article-title":"Prognostic trends and current challenges in candidemia: a comparative analysis of two multicenter cohorts within the past decade","volume":"9","author":"Agnelli","year":"2023","journal-title":"J. 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