目的：胰腺癌（PC）是一种毁灭性的恶性肿瘤，其特点是侵袭性和预后不良。然而，PC 与外周代谢物的关系尚未得到充分研究。该研究旨在探讨 PC 与外周代谢物谱之间的因果关系。方法：利用公开的全基因组关联研究（GWAS）数据，我们进行了双向双样本孟德尔随机化（MR）分析。主要分析采用逆方差加权（IVW）方法。为了解决有关水平多效性的潜在问题，我们还采用了补充方法，例如最大似然法、加权中值、MR-Egger 回归以及 MR 多效性残差和和离群值 (MR-PRESSO)。结果：我们确定了 20 种基因决定的外周代谢物与 PC 存在因果关系，其中高密度脂蛋白 (HDL) 和极低密度脂蛋白 (VLDL) 颗粒占绝大多数。具体而言，HDL 颗粒表现出较高的 PC 风险，而 VLDL 颗粒则表现出相反的模式。反向 MR 分析强调了 PC 导致 17 种外周代谢物发生显着变化，包括支链氨基酸和甘油磷脂衍生物。交叉引用双向 MR 结果揭示了 PC 和 X-02269 的相互因果关系，这可能在 PC 开发中形成自我延续的循环。此外，1-花生四烯酰甘油磷酸胆碱表明 PC 风险降低，并在 PC 影响下增加，可能充当负反馈调节剂。结论：我们的研究结果表明胰腺癌和外周代谢物之间存在复杂的相互作用，对于了解胰腺癌的病因和确定新的早期诊断和治疗靶点具有潜在的意义。此外，X-02269 可能在 PC 的发病和进展中发挥关键作用。版权所有 © 2023 Sun、Xu、Liu、Zhou、Li 和 Sun。

Aim: Pancreatic cancer (PC) is a devastating malignancy characterized by its aggressive nature and poor prognosis. However, the relationship of PC with peripheral metabolites remains not fully investigated. The study aimed to explore the causal linkage between PC and peripheral metabolite profiles. Methods: Employing publicly accessible genome-wide association studies (GWAS) data, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis. The primary analysis employed the inverse-variance weighted (IVW) method. To address potential concerns about horizontal pleiotropy, we also employed supplementary methods such as maximum likelihood, weighted median, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO). Results: We ascertained 20 genetically determined peripheral metabolites with causal linkages to PC while high-density lipoprotein (HDL) and very low-density lipoprotein (VLDL) particles accounted for the vast majority. Specifically, HDL particles exhibited an elevated PC risk while VLDL particles displayed an opposing pattern. The converse MR analysis underscored a notable alteration in 17 peripheral metabolites due to PC, including branch chain amino acids and derivatives of glycerophospholipid. Cross-referencing the bidirectional MR results revealed a reciprocal causation of PC and X-02269 which might form a self-perpetuating loop in PC development. Additionally, 1-arachidonoylglycerophosphocholine indicated a reduced PC risk and an increase under PC influence, possibly serving as a negative feedback regulator. Conclusion: Our findings suggest a complex interplay between pancreatic cancer and peripheral metabolites, with potential implications for understanding the etiology of pancreatic cancer and identifying novel early diagnosis and therapeutic targets. Moreover, X-02269 may hold a pivotal role in PC onset and progression.Copyright © 2023 Sun, Xu, Liu, Zhou, Li and Sun.