{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T13:54:31Z","timestamp":1788184471990,"version":"build-2803163510"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"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. Immunol."],"abstract":"<jats:p>Systemic sclerosis (SSc) is a rare and complex autoimmune disease characterized by fibrosis of the skin and internal organs as well as vascular abnormalities. Studies have suggested that paclitaxel may induce adverse reactions resembling systemic sclerosis; however, the underlying mechanisms remain not fully understood. We retrieved reports of paclitaxel-associated SSc from the FDA Adverse Event Reporting System (FAERS). Potential shared targets between paclitaxel and SSc were identified through network toxicology analysis. Mendelian randomization (MR) was then used to explore associations between these targets and SSc susceptibility. Disproportionality analyses demonstrated significant safety signals linking paclitaxel with SSc, scleroderma, and scleroderma-like reactions. A total of 76 overlapping targets were identified between paclitaxel and SSc. Based on expression quantitative trait loci (eQTL) from the IEU OpenGWAS database, MR analysis suggested 11 targets potentially associated with SSc susceptibility. Functional enrichment analyses revealed that these genes were involved in oxidative stress response, regulation of cell death, lipid metabolism, and apoptosis. Among them, AKT1 and BCL2 were highlighted as central nodes in the protein\u2013protein interaction network, representing candidate targets for further investigation. Molecular docking simulations provided exploratory computational evidence of potential interactions, which do not confirm functional or mechanistic roles. Overall, this study systematically explored potential molecular targets related to paclitaxel-associated SSc and provides hypothesis-generating insights that may guide future mechanistic studies and risk assessment strategies.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1696820","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:34:27Z","timestamp":1783575267000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrative analysis of FAERS, network toxicology, and Mendelian randomization identifies potential targets in paclitaxel-associated systemic sclerosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Xinfeng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Shanxi Province Cancer Hospital\/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences\/Cancer Hospital Affiliated to Shanxi Medical University","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Shanxi Province Cancer Hospital\/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences\/Cancer Hospital Affiliated to Shanxi Medical University","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-022-08946-w","article-title":"Systemic sclerosis-specific antibodies: Novel and classical biomarkers","volume":"64","author":"Cavazzana","year":"2023","journal-title":"Clin Rev Allergy Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-023-01032-1","article-title":"Back to the future: Targeting the extracellular matrix to treat systemic sclerosis","volume":"19","author":"Leask","year":"2023","journal-title":"Nat Rev Rheumatol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.5114\/pg.2017.70467","article-title":"Systemic sclerosis and the gastrointestinal tract","volume":"12","author":"Walecka","year":"2017","journal-title":"Prz Gastroenterol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2021.10.065","article-title":"Systemic sclerosis in adults. Part I: Clinical features and pathogenesis","volume":"87","author":"Jerjen","year":"2022","journal-title":"J Am Acad Dermatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2021.102727","article-title":"Insights into the knowledge of complex diseases: Environmental infectious\/toxic agents as potential etiopathogenetic factors of systemic sclerosis","volume":"124","author":"Ferri","year":"2021","journal-title":"J Autoimmun"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.alit.2021.08.005","article-title":"Drug-induced scleroderma-like lesion","volume":"71","author":"Hamaguchi","year":"2022","journal-title":"Allergol Int"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2022.103157","article-title":"Drugs associated with systemic sclerosis: An updated list of suspected drugs using the WHO pharmacovigilance database","volume":"21","author":"Dumont","year":"2022","journal-title":"Autoimmun Rev"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1257802","article-title":"Distinct molecular subtypes of systemic sclerosis and gene signature with diagnostic capability","volume":"14","author":"Wang","year":"2023","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-022-06364-z","article-title":"Paclitaxel-induced diffuse scleroderma with possible scleroderma-renal crisis: A case report and literature review of taxanes-induced scleroderma","volume":"41","author":"Ketpueak","year":"2022","journal-title":"Clin Rheumatol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1111\/ajd.12719","article-title":"Paclitaxel-related scleredema-like skin changes in a patient with breast cancer","volume":"59","author":"Tani","year":"2018","journal-title":"Australas J Dermatol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1016\/j.jaip.2020.09.021","article-title":"Emerging causes of drug-induced anaphylaxis: A review of anaphylaxis-associated reports in the FDA adverse event reporting system (FAERS)","volume":"9","author":"Yu","year":"2021","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B12","doi-asserted-by":"publisher","first-page":"796","DOI":"10.7150\/ijms.6048","article-title":"Data mining of the public version of the FDA adverse event reporting system","volume":"10","author":"Sakaeda","year":"2013","journal-title":"Int J Med Sci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2024.104398","article-title":"Safety of immune checkpoint inhibitors: An updated comprehensive disproportionality analysis and meta-analysis","volume":"200","author":"Tyagi","year":"2024","journal-title":"Crit Rev Oncol Hematol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2019-000104","article-title":"T-cell lymphoma secondary to checkpoint inhibitor therapy","volume":"8","author":"Anand","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-022-02568-y","article-title":"Patterns of toxicity burden for FDA-approved immune checkpoint inhibitors in the United States","volume":"42","author":"Yang","year":"2023","journal-title":"J Exp Clin Cancer Res"},{"key":"B16","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1186\/s12967-023-04474-z","article-title":"Identification of potential drug targets for rheumatoid arthritis from genetic insights: A Mendelian randomization study","volume":"21","author":"Cao","year":"2023","journal-title":"J Transl Med"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/s0749-2081(16)30035-3","article-title":"Overview of paclitaxel (TAXOL)","volume":"9","author":"Martin","year":"1993","journal-title":"Semin Oncol Nurs"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1097\/cco.0000000000001056","article-title":"Diligent use of MedDRA terminology and preferred term selection in safety reports of clinical trials","volume":"36","author":"Fey","year":"2024","journal-title":"Curr Opin Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1231320","article-title":"Risk factors for drug-related acute pancreatitis: An analysis of the FDA adverse event reporting system (FAERS)","volume":"14","author":"Zhang","year":"2023","journal-title":"Front Pharmacol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1080\/14740338.2023.2278700","article-title":"Drug-induced hypoglycemia: A disproportionality analysis of the FAERS database","volume":"23","author":"Li","year":"2024","journal-title":"Expert Opin Drug Saf"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa971","article-title":"PubChem in 2021: New data content and improved web interfaces","volume":"49","author":"Kim","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp937","article-title":"STITCH 2: An interaction network database for small molecules and proteins","volume":"38","author":"Kuhn","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz1021","article-title":"The DisGeNET knowledge platform for disease genomics: 2019 update","volume":"48","author":"Pi\u00f1ero","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.7554\/elife.34408","article-title":"The MR-Base platform supports systematic causal inference across the human phenome","volume":"7","author":"Hemani","year":"2018","journal-title":"Elife"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen provides genetic insights from a well-phenotyped isolated population","volume":"613","author":"Kurki","year":"2023","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac1010","article-title":"The NHGRI-EBI GWAS Catalog: Knowledgebase and deposition resource","volume":"51","author":"Sollis","year":"2023","journal-title":"Nucleic Acids Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.xinn.2021.100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation (Camb)"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac394","article-title":"CB-Dock2: Improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting","volume":"50","author":"Liu","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1007\/s42535-023-00587-4","article-title":"In silico molecular docking analysis and ADME prediction of cow urine derived 1-heneicosanol against some bacterial proteins","volume":"37","author":"Nautiyal","year":"2024","journal-title":"Vegetos"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3109\/02841861003702510","article-title":"Scleroderma induced by paclitaxel","volume":"49","author":"Pedersen","year":"2010","journal-title":"Acta Oncol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23031142","article-title":"Paclitaxel-induced epidermal alterations: An in vitro preclinical assessment in primary keratinocytes and in a 3D epidermis model","volume":"23","author":"Montero","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0020354","article-title":"Paclitaxel modulates TGFbeta signaling in scleroderma skin grafts in immunodeficient mice","volume":"2","author":"Liu","year":"2005","journal-title":"PloS Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02452","article-title":"Unraveling SSc pathophysiology; The myofibroblast","volume":"9","author":"van Caam","year":"2018","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2008.39","article-title":"Akt blockade downregulates collagen and upregulates MMP1 in human dermal fibroblasts","volume":"128","author":"Bujor","year":"2008","journal-title":"J Invest Dermatol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/cdd.2017.161","article-title":"The BCL-2 arbiters of apoptosis and their growing role as cancer targets","volume":"25","author":"Adams","year":"2018","journal-title":"Cell Death Differ"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26178394","article-title":"Fibrotic disease of the skin and lung: Shared pathways, environmental drivers, and therapeutic opportunities in a changing climate","volume":"26","author":"Grafanaki","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1395982","article-title":"Adverse drug reactions in neonates: A brief analysis of the FDA adverse event reporting system","volume":"15","author":"Byskov","year":"2024","journal-title":"Front Pharmacol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1696820\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:34:28Z","timestamp":1783575268000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1696820\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":39,"alternative-id":["10.3389\/fimmu.2026.1696820"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1696820","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,9]]},"article-number":"1696820"}}