{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T07:06:46Z","timestamp":1774940806758,"version":"3.50.1"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"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. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Gastric cancer (GC) is a leading cause of cancer mortality worldwide, and dietary factors like mycotoxins play a significant role in its etiology. Zearalenone (ZEN), a widespread grain contaminant, is a suspected carcinogen; however, its molecular mechanisms in GC remain unclear. This study used an integrated systems toxicology approach to identify key targets and pathways of ZEN-induced GC and validate the findings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>An integrated computational and experimental strategy was used. GC-related genes were identified from Gene Expression Omnibus (GEO) datasets using differential expression and weighted gene co-expression network analysis (WGCNA). ZEN targets were obtained from multiple databases. Common targets were analyzed for pathway enrichment and protein-protein interactions. Eleven machine learning algorithms screened for core driver genes among these common targets. The binding stability of ZEN to core targets was assessed using molecular docking and 100-ns molecular dynamics simulations. In vitro functional validation was performed using CCK-8, colony formation, EdU, and wound healing assays on the human GC cell line MKN-45.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified 157 common targets of ZEN and GC. Enrichment analysis highlighted key pathways, including P13K-Akt signaling and glycolysis. Machine learning identified six core driver genes (COL1A1, INHBA, PKM2, THBS2, MFAP2, and CPA2) with high diagnostic potential (AUC&amp;gt;0.85). Molecular simulations confirmed ZEN forms stable complexes with core targets, particularly PKM2 and THBS2. In vitro experiments showed low concentrations of ZEN (40-80 nM) significantly promoted proliferation and migration of MKN-45 cells, demonstrating a hormetic effect.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study suggests ZEN promotes GC progression through a multi-level network. ZEN may directly modulate key effector proteins such as PKM2 to induce metabolic reprogramming. The observed hormetic pro-proliferative and pro-migratory responses were linked to the pre-existing activation state of the PI3K\/Akt pathway. These findings provide novel mechanistic insights into the carcinogenic risk of ZEN.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1762191","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T05:34:43Z","timestamp":1774935283000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Systems toxicology unravels multi-tiered carcinogenic networks of zearalenone in gastric cancer"],"prefix":"10.3389","volume":"16","author":[{"given":"Hangbin","family":"Zheng","sequence":"first","affiliation":[{"name":"Affiliated People\u2019s Hospital, Fujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Fujian-Hong Kong-Macau-Taiwan Collaborative Laboratory for the Inheritance and Innovation of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, The Academy of Rehabilitation Industry, Fujian University of Traditional Chinese Medicine","place":["Fuzhou, Fujian, China"]},{"name":"The First School of Clinical Medicine, The Second People\u2019s Hospital of Fujian Province, Fujian University of Traditional Chinese Medicine","place":["Fuzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shun","family":"Chen","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, The Second People\u2019s Hospital of Fujian Province, Fujian University of Traditional Chinese Medicine","place":["Fuzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo","family":"Lin","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, The Second People\u2019s Hospital of Fujian Province, Fujian University of Traditional Chinese Medicine","place":["Fuzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenxin","family":"Huang","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, The Second People\u2019s Hospital of Fujian Province, Fujian University of Traditional Chinese Medicine","place":["Fuzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihui","family":"Guo","sequence":"additional","affiliation":[{"name":"Health Medical Center, The 910th Hospital of the People\u2019s Liberation Army Joint Logistics Support Force","place":["Quanzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Integrative Medicine, Fujian University of Traditional Chinese Medicine","place":["Fuzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyi","family":"Jin","sequence":"additional","affiliation":[{"name":"College of Integrative Medicine, Fujian University of Traditional Chinese Medicine","place":["Fuzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Lin","sequence":"additional","affiliation":[{"name":"Affiliated People\u2019s Hospital, Fujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Fujian-Hong Kong-Macau-Taiwan Collaborative Laboratory for the Inheritance and Innovation of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, The Academy of Rehabilitation Industry, Fujian University of Traditional Chinese Medicine","place":["Fuzhou, Fujian, China"]},{"name":"The Academy of Rehabilitation Industry, Fujian University of Traditional Chinese Medicine","place":["Fuzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Lin","sequence":"additional","affiliation":[{"name":"Affiliated People\u2019s Hospital, Fujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Fujian-Hong Kong-Macau-Taiwan Collaborative Laboratory for the Inheritance and Innovation of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, The Academy of Rehabilitation Industry, Fujian University of Traditional Chinese Medicine","place":["Fuzhou, Fujian, China"]},{"name":"College of Integrative Medicine, Fujian University of Traditional Chinese Medicine","place":["Fuzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liwu","family":"Chen","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, The Second People\u2019s Hospital of Fujian Province, Fujian University of Traditional Chinese Medicine","place":["Fuzhou, Fujian, 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