据观察，肺腺癌 (LUAD) 在发病率、预后和治疗反应方面存在显着的性别差异。然而，造成这些差异的分子机制尚未得到广泛研究。 使用样本特异性基因调控网络方法分析来自基因型组织表达项目 (GTEx) 的非癌性人肺样本和肺腺癌原发性肿瘤的 RNA 测序数据来自癌症基因组图谱 (TCGA) 的样本；结果在独立数据上得到了验证。我们发现，在健康肺组织和肿瘤中，与关键生物途径（包括细胞增殖、免疫反应和药物代谢）相关的基因在男性和女性之间受到差异性调节，并且这些调节差异进一步受到烟草的干扰吸烟。我们还发现临床上可操作的癌基因和肿瘤抑制基因（包括 AKT2 和 KRAS）的转录因子靶向模式存在显着的性别偏见。利用健康样本和肿瘤样本之间差异调节的基因，结合药物再利用工具，我们鉴定了几种可能具有性别偏见的癌症治疗功效的小分子药物，并使用独立的细胞系数据库进一步验证了这一观察结果。这些发现强调了在制定疾病预防和管理策略时将性别作为生物变量并考虑基因调控过程的重要性。© 2024。作者。

Lung adenocarcinoma (LUAD) has been observed to have significant sex differences in incidence, prognosis, and response to therapy. However, the molecular mechanisms responsible for these disparities have not been investigated extensively.Sample-specific gene regulatory network methods were used to analyze RNA sequencing data from non-cancerous human lung samples from The Genotype Tissue Expression Project (GTEx) and lung adenocarcinoma primary tumor samples from The Cancer Genome Atlas (TCGA); results were validated on independent data.We found that genes associated with key biological pathways including cell proliferation, immune response and drug metabolism are differentially regulated between males and females in both healthy lung tissue and tumor, and that these regulatory differences are further perturbed by tobacco smoking. We also discovered significant sex bias in transcription factor targeting patterns of clinically actionable oncogenes and tumor suppressor genes, including AKT2 and KRAS. Using differentially regulated genes between healthy and tumor samples in conjunction with a drug repurposing tool, we identified several small-molecule drugs that might have sex-biased efficacy as cancer therapeutics and further validated this observation using an independent cell line database.These findings underscore the importance of including sex as a biological variable and considering gene regulatory processes in developing strategies for disease prevention and management.© 2024. The Author(s).