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The tobacco-specific metabolite cotinine may promote cancer progression through mechanisms such as chronic inflammation and genomic instability, but its precise molecular targets and interactions remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated network toxicology and multi-omics for target prediction, validated by molecular biology experiments and dynamic simulations. The workflow included database screening of cotinine-related targets, identification of key modules via single-cell analysis and hdWGCNA, integration of differential gene analysis to obtain potential targets, determination of core targets using protein-protein interaction networks, pathway enrichment and machine learning, transcriptomic profiling of cotinine-induced cell type-specific pathway regulation in H8 and HeLa cells, and further validation through molecular docking, molecular dynamics simulations, and in silico knockout.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Initial screening identified 151 cotinine-related targets, refined to 17 key candidates via integrated multi-omics analysis and machine learning. Molecular studies revealed multi-level carcinogenic mechanisms: in H8 cells, cotinine promoted tumorigenesis via chronic inflammation, differentiation defects, ECM remodeling, and signaling dysregulation; in HeLa cells, it accelerated progression\/metastasis through dysregulated proliferation, matrix degradation, impaired metal ion transport, and cytokine storms. Validated targets\u2014\n                      <jats:italic>KAT2B<\/jats:italic>\n                      (in H8 cells) and\n                      <jats:italic>CA9<\/jats:italic>\n                      ,\n                      <jats:italic>CCNB1<\/jats:italic>\n                      ,\n                      <jats:italic>LAGE3<\/jats:italic>\n                      (in HeLa cells)\u2014were significantly downregulated in cervical tumors. Molecular docking and dynamics simulations confirmed stable cotinine-target binding.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study systematically demonstrates that cotinine exerts its carcinogenic effects by targeting\n                      <jats:italic>KAT2B<\/jats:italic>\n                      ,\n                      <jats:italic>CA9<\/jats:italic>\n                      ,\n                      <jats:italic>CCNB1<\/jats:italic>\n                      , and\n                      <jats:italic>LAGE3<\/jats:italic>\n                      , thereby dysregulating multiple signaling pathways to induce tumorigenesis in epithelial cells and accelerate progression\/metastasis in malignant cells. Elucidation of this multi-target toxicity mechanism provides a critical theoretical foundation for developing targeted detoxification strategies against tobacco-associated cervical cancer.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s12672-026-05375-5","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T11:44:00Z","timestamp":1781264640000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell-specific multi-target mechanisms of cotinine in cervical cancer oncogenesis and progression"],"prefix":"10.1007","volume":"17","author":[{"given":"Jiaming","family":"Cheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyang","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changsong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"issue":"2","key":"5375_CR1","first-page":"229","volume":"112","author":"A Buskwofie","year":"2020","unstructured":"Buskwofie A, David-West G, Clare CA. 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