女性患非小细胞肺癌（NSCLC）的风险更高，然而其潜在原因尚不清楚。我们在cRaf转基因小鼠的肺肿瘤中进行了全基因组扫描，并鉴定了miRNA、转录因子和激素受体依赖的基因调控。我们通过免疫组化确认了激素受体，并通过考虑经验证的miRNA–基因和转录因子–miRNA/基因靶点构建了调控基因网络。通过生物信息学、基因组足迹和基因富集分析，建立了性别特异性的肺肿瘤生长回路。转化研究涉及大规模的NSCLC患者群体。我们评估了小鼠和人类性别特异性NSCLC基因调控的共性，并确定了它们在Kaplan-Meier生存统计和COX比例风险回归分析中的预后价值。cRaf激酶的过表达在雌性中引发了异常的8倍增长，112个差异表达基因（DEGs）中近70%为女性特异性。我们鉴定了肿瘤生成基因、肿瘤miRNA、肿瘤抑制基因、细胞周期调控因子和MAPK/EGFR信号分子，它们引起了NSCLC的性别差异，并解析了一种保护雄性免受加速肿瘤生长的调控基因网络。令人惊讶的是，41%的DEGs是激素受体的靶点，其中大多数（85%）是雌激素受体（ER）依赖的。我们在大规模的NSCLC患者群体中确证了ER的作用，并在临床肿瘤样本中验证了cRaf诱导的40%的DEGs。我们报道了在肿瘤生长中引发性别差异的分子连线。这使我们提出了通过联合阻断ER、CDK1和精氨酸酶2在NSCLC中发展分子靶向疗法。我们感谢德国下萨克森州文化和科学部以及大众汽车基金会（25A.5-7251-99-3/00）对JB的经济支持，并感谢中国国家留学基金委员会对SZ的资助（202008080022）。本出版物是作为“开放获取出版费用”计划的一部分由德意志研究协会（DFG）资助的。版权所有 © 2023 作者。Elsevier B.V.出版。保留所有权利。

Women are at greater risk of developing non-small cell lung cancer (NSCLC), yet the underlying causes remain unclear.We performed whole genome scans in lung tumours of cRaf transgenic mice and identified miRNA, transcription factor and hormone receptor dependent gene regulations. We confirmed hormone receptors by immunohistochemistry and constructed regulatory gene networks by considering experimentally validated miRNA-gene and transcription factor-miRNA/gene targets. Bioinformatics, genomic foot-printing and gene enrichment analysis established sex-specific circuits of lung tumour growth. Translational research involved a large cohort of NSCLC patients. We evaluated commonalities in sex-specific NSCLC gene regulations between mice and humans and determined their prognostic value in Kaplan-Meier survival statistics and COX proportional hazard regression analysis.Overexpression of the cRaf kinase elicited an extraordinary 8-fold increase in tumour growth among females, and nearly 70% of the 112 differentially expressed genes (DEGs) were female specific. We identified oncogenes, oncomirs, tumour suppressors, cell cycle regulators and MAPK/EGFR signalling molecules, which prompted sex-based differences in NSCLC, and we deciphered a regulatory gene-network, which protected males from accelerated tumour growth. Strikingly, 41% of DEGs are targets of hormone receptors, and the majority (85%) are oestrogen receptor (ER) dependent. We confirmed the role of ER in a large cohort of NSCLC patients and validated 40% of DEGs induced by cRaf in clinical tumour samples.We report the molecular wiring that prompted sex disparities in tumour growth. This allowed us to propose the development of molecular targeted therapies by jointly blocking ER, CDK1 and arginase 2 in NSCLC.We gratefully acknowledge the financial support of the Lower Saxony Ministry of Culture and Sciences and Volkswagen Foundation, Germany to JB (25A.5-7251-99-3/00) and of the Chinese Scholarship Council to SZ (202008080022). This publication is funded by the Deutsche Forschungsgemeinschaft (DFG) as part of the "Open Access Publikationskosten" program.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.