{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:12:05Z","timestamp":1790093525637,"version":"4.0.1"},"reference-count":63,"publisher":"American Chemical Society (ACS)","issue":"37","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Multidisciplinary Innovation Team Project in Traditional Chinese Medicine","award":["ZYYCXTD-D-202407"],"award-info":[{"award-number":["ZYYCXTD-D-202407"]}]},{"name":"Heilongjiang Provincial Key Research and Development Plan","award":["2022ZX02C04"],"award-info":[{"award-number":["2022ZX02C04"]}]},{"name":"Lateral Project of Dong'e Ejiao Co., Ltd.","award":["22042240002"],"award-info":[{"award-number":["22042240002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Benzo[a]pyrene (Bap), a prominent carcinogen found in tobacco smoke and air pollution, is closely associated with lung adenocarcinoma (LUAD) and subsequent depression, though the mechanism underlying this comorbidity remains unclear. LUAD patients were categorized based on depression-related gene expression. Prognostic genes identified through machine learning were cross-referenced with predicted Bap targets. Mendelian randomization (MR) evaluated the causal relationship between RNASE1 and depression. Single-cell RNA sequencing (scRNA-seq), molecular docking, and 100 ns molecular dynamics (MD) simulations (using the CHARMM36 force field and TIP3P water model) were conducted, followed by analyses of RMSD, RMSF, Rg, SASA, and Gibbs free energy landscape. A Bap-exposed mouse model was used to validate key gene expression and depression-like behaviors in vivo. Consensus clustering based on 52 depression-related genes stratified the TCGA-LUAD cohort into two gene signature-based molecular subtypes with distinct expression patterns and prognostic outcomes. Cluster 1 represented a favorable-prognosis subtype with better disease-free survival, whereas Cluster 2 represented a poor-prognosis subtype with stronger depression-related transcriptomic features; however, these clusters should not be interpreted as clinically confirmed depression subgroups because TCGA lacks psychiatric assessment data. Among 57 depression-related prognostic genes intersected with 375 Bap targets, five genes overlapped: CLEC7A, NEK2, RNASE1, ITGAL, and CPA3. MR confirmed that elevated lung RNASE1 increased depression risk (IVW: OR = 1.008, 95% CI: 1.002\u20131.014, P = 0.005), while CLEC7A and other genes showed no causal link. scRNA-seq localized RNASE1 upregulation to tumor epithelial cells, monocytes, and macrophages. Docking and MD analyses supported stable Bap\u2013RNASE1 binding, involving hydrophobic interactions with key residues and a dominant low-energy conformational state. In vivo, Bap-exposed mice showed prolonged immobility time in the tail suspension test, fewer open-arm entries, and reduced open-arm time in the elevated plus-maze test, accompanied by elevated WBC, MPV, PDW, and increased lung RNASE1 protein expression. Bap may contribute to LUAD-related depression through RNASE1 upregulation. This provides molecular-level mechanistic insight into the cancer\u2013depression comorbidity driven by environmental carcinogens.<\/jats:p>","DOI":"10.1021\/acsomega.6c04956","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:01:36Z","timestamp":1789185696000},"page":"55704-55726","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Systems\nToxicology Analysis and Molecular\nDynamics Study Reveal the Potential Mechanism by which Benzo[a]pyrene\nContributes to Depression in Lung Adenocarcinoma via RNASE1 Upregulation"],"prefix":"10.1021","volume":"11","author":[{"given":"Jingzhe","family":"Gao","sequence":"first","affiliation":[{"name":"Heilongjiang University of Chinese Medicine , , Heping Road 24 , ,","place":["Harbin, China, 150040"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuxiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Heilongjiang University of Chinese Medicine , , Heping Road 24 , ,","place":["Harbin, China, 150040"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4702-3718","authenticated-orcid":true,"given":"Kunshuang","family":"Shen","sequence":"additional","affiliation":[{"name":"Heilongjiang University of Chinese Medicine , , Heping Road 24 , ,","place":["Harbin, China, 150040"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengnan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Heilongjiang University of Chinese Medicine , , Heping Road 24 , ,","place":["Harbin, China, 150040"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibin","family":"Liu","sequence":"additional","affiliation":[{"name":"Dong\u2019e Ejiao Co., Ltd. , , E \u2018Jiao Road 78, Dong \u2018e , ,","place":["Liaocheng, China, 252200"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoyu","family":"Xie","sequence":"additional","affiliation":[{"name":"Heilongjiang University of Chinese Medicine , , Heping Road 24 , ,","place":["Harbin, China, 150040"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjun","family":"Gu","sequence":"additional","affiliation":[{"name":"Dong\u2019e Ejiao Co., Ltd. , , E \u2018Jiao Road 78, Dong \u2018e , ,","place":["Liaocheng, China, 252200"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Zhang","sequence":"additional","affiliation":[{"name":"Heilongjiang University of Chinese Medicine , , Heping Road 24 , ,","place":["Harbin, China, 150040"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Sun","sequence":"additional","affiliation":[{"name":"Heilongjiang University of Chinese Medicine , , Heping Road 24 , ,","place":["Harbin, China, 150040"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangli","family":"Yan","sequence":"additional","affiliation":[{"name":"Heilongjiang University of Chinese Medicine , , Heping Road 24 , ,","place":["Harbin, China, 150040"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xijun","family":"Wang","sequence":"additional","affiliation":[{"name":"Heilongjiang University of Chinese Medicine , , Heping Road 24 , ,","place":["Harbin, China, 150040"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"issue":"3","key":"2026092210565222200_cit1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN\nestimates of incidence and mortality worldwide for 36 cancers in 185\ncountries","volume":"74","author":"Bray","year":"2024","journal-title":"Ca-Cancer J. 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