与其他广泛筛查的癌症（乳腺癌、结直肠癌、宫颈癌、前列腺癌和皮肤癌）不同，肺结节活检阳性筛查的临床并发症发病率较高。因此，非侵入性诊断生物标志物的开发可以显着增强对高危患者的肺癌管理。在这里，我们利用孟德尔随机化 (MR) 研究血浆蛋白质组和代谢组，寻找与肺癌相关的潜在生物标志物。利用双向 MR 和共定位分析，我们发现了新的关联，强调肺腺癌 (LUAD) 中血浆蛋白 SFTPB 和 KDELC2 之间的负相关，以及 TCL1A 与肺鳞状细胞癌 (LUSC) 和 CNTN1 与小细胞肺癌的正相关。小细胞肺癌）。此外，我们的工作揭示了 LUAD 和 LUSC 中可可碱和副黄嘌呤等代谢物之间以及副黄嘌呤相关比率之间存在显着的负相关性。相反，咖啡因/副黄嘌呤和花生四烯酸 (20:4n6)/副黄嘌呤比率与这些癌症类型呈正相关。通过正常肺组织的单细胞测序数据，我们进一步探讨肺组织特异性蛋白SFTPB在癌变中的作用。这些发现为肺癌病因学提供了新的见解，有可能指导诊断生物标志物和治疗方法的开发。© 作者 2024。由牛津大学出版社出版。版权所有。如需权限，请发送电子邮件至：journals.permissions@oup.com。

Unlike other cancers with widespread screening (breast, colorectal, cervical, prostate, and skin), lung nodule biopsies for positive screenings have higher morbidity with clinical complications. Development of non-invasive diagnostic biomarkers could thereby significantly enhance lung cancer management for at-risk patients. Here, we leverage Mendelian Randomization (MR) to investigate the plasma proteome and metabolome for potential biomarkers relevant to lung cancer. Utilizing bidirectional MR and co-localization analyses, we identify novel associations, highlighting inverse relationships between plasma proteins SFTPB and KDELC2 in lung adenocarcinoma (LUAD) and positive associations of TCL1A with lung squamous cell carcinoma (LUSC) and CNTN1 with small cell lung cancer (SCLC). Additionally, our work reveals significant negative correlations between metabolites such as theobromine and paraxanthine, along with paraxanthine-related ratios, in both LUAD and LUSC. Conversely, positive correlations are found in caffeine/paraxanthine and arachidonate (20:4n6)/paraxanthine ratios with these cancer types. Through single-cell sequencing data of normal lung tissue, we further explore the role of lung tissue-specific protein SFTPB in carcinogenesis. These findings offer new insights into lung cancer etiology, potentially guiding the development of diagnostic biomarkers and therapeutic approaches.© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.