{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T15:48:29Z","timestamp":1790351309122,"version":"4.1.0"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"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>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Drug-induced cheilitis represents an inadequately comprehended adverse reaction, with limited understanding of its underlying mechanisms. This study employs an integrative approach, combining pharmacovigilance, network toxicology, and molecular docking methodologies, to systematically examine the phenomenon of drug-associated cheilitis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted an analysis of 5,007 cheilitis reports obtained from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FDA Adverse Event Reporting System, 2004\u20132025) by employing disproportionality analysis and multivariate logistic regression techniques. Utilizing network toxicology, we constructed protein\u2013protein interaction networks and identified enriched pathways. Furthermore, molecular docking and 500\u00a0ns molecular dynamics simulations were employed to validate the binding interactions between high-risk pharmacological agents and core molecular targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Thirty-eight pharmaceuticals demonstrated significant associations with cheilitis, with isotretinoin being the most frequently reported (ROR = 42.61) and crisaborole exhibiting the most pronounced signal (ROR = 550.48). Female sex emerged as an independent risk factor (OR = 0.771), whereas age and weight appeared to offer modest protective effects. Network analysis identified Interleukin 6 (IL6), tumor necrosis factor (TNF), AKT Serine\/Threonine Kinase 1 (AKT1), Vascular Endothelial Growth Factor A (VEGFA) and Signal Transducer and Activator of Transcription 3 (STAT3) as central targets, with notable enrichment in the IL-17, TNF, and PI3K-Akt signaling pathways. Molecular docking studies indicated strong binding affinities (ranging from \u22128.1 to \u22126.2\u00a0kcal\/mol), particularly for the afatinib-EGFR and capecitabine-IL-6 interactions. Molecular dynamics simulations confirmed the stability of these complexes, with MM\/PBSA analysis highlighting key stabilizing residues. ADMET profiling predicted a high risk of drug-induced liver injury for four compounds, while lamotrigine demonstrated a favorable safety profile.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This integrative framework connects population-level indicators with mechanistic forecasts, providing a translational model for comprehending, predicting, and managing drug-induced cheilitis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1757807","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T06:38:12Z","timestamp":1773988692000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["An integrative pharmacovigilance, network toxicology and molecular docking study on drug-induced cheilitis"],"prefix":"10.3389","volume":"17","author":[{"given":"Xuefeng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Stomatology, The Affiliated Hospital of Chengde Medical University","place":["Chengde, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangzhi","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Stomatology, The Affiliated Hospital of Chengde Medical University","place":["Chengde, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingxue","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Stomatology, The Affiliated Hospital of Chengde Medical University","place":["Chengde, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Stomatology, The Affiliated Hospital of Chengde Medical University","place":["Chengde, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery, The Affiliated Hospital of Chengde Medical University","place":["Chengde, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Affiliated Hospital of Chengde Medical University","place":["Chengde, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanbo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Stomatology, The Affiliated Hospital of Chengde Medical University","place":["Chengde, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s40360-023-00657-y","article-title":"Medication-induced osteonecrosis of the jaw: a review of cases from the food and drug administration adverse event reporting system (FAERS)","volume":"24","author":"Ahdi","year":"2023","journal-title":"BMC Pharmacol. 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