2026-10-12T17:01:27Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33652789 2026-09-12T03:04:22Z category_12 category_14 category_873 category_46 category_734 category_64 category_122 portal_63 item_type_3 month_year_09_2026

Integrated Systems Toxicology Analysis and Molecular Dynamics Study Reveal the Potential Mechanism by which Benzo[a]pyrene Contributes to Depression in Lung Adenocarcinoma via RNASE1 Upregulation Jingzhe Gao (24160758) Fuxiang Huang (18274678) Kunshuang Shen (14016111) Shengnan Zhu (9019235) Haibin Liu (403499) Yaoyu Xie (22533761) Jianjun Gu (736122) Ning Zhang (23771) Hui Sun (107933) Guangli Yan (413257) Xijun Wang (413258) Cell Biology Molecular Biology Chemical Sciences not elsewhere classified Immunology Biological Sciences not elsewhere classified Cancer Mental Health two gene signature tumor epithelial cells tip3p water model prominent carcinogen found level mechanistic insight involving hydrophobic interactions exposed mouse model energy conformational state distinct expression patterns comorbidity remains unclear charmm36 force field cell rna sequencing related transcriptomic features related gene expression five genes overlapped consensus clustering based tail suspension test related genes stratified prognostic genes identified predicted bap targets based molecular subtypes bap may contribute 375 bap targets cluster 1 represented 002 – 1 among 57 depression genes showed categorized based provides molecular prognostic outcomes maze test related depression bap ), tobacco smoke reduced open prognosis subtype potential mechanism p </ mendelian randomization mechanism underlying machine learning lung adenocarcinoma like behaviors key residues free survival fewer open environmental carcinogens elevated wbc elevated plus 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: 1.002–1.014, <i>P</i> = 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–RNASE1 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–depression comorbidity driven by environmental carcinogens. 2026-09-11T00:00:00Z Dataset Dataset 10.1021/acsomega.6c04956.s002 https://figshare.com/articles/dataset/Integrated_Systems_Toxicology_Analysis_and_Molecular_Dynamics_Study_Reveal_the_Potential_Mechanism_by_which_Benzo_a_pyrene_Contributes_to_Depression_in_Lung_Adenocarcinoma_via_RNASE1_Upregulation/33652789 CC BY-NC 4.0