有限的研究集中在二氢尿苷合酶 (DUS) 家族成员在人类肿瘤中的作用。我们之前的研究结果表明，二氢尿苷合酶 4 样 (DUS4L) 对肺腺癌 (LUAD) A549 细胞的细胞增殖和凋亡有影响，但其在 LUAD 中更广泛的功能和调节机制仍不清楚。使用 LUAD 组织微阵列和免疫组织化学 (IHC)通过染色，我们验证了 LUAD 患者中 DUS4L 蛋白表达水平的变化并评估了其临床意义。使用短发夹 RNA (shRNA) 对抗 DUS4L (sh-DUS4L-2)、LUAD 细胞系、细胞功能测定（包括伤口愈合、Transwell 迁移和侵袭、集落形成和细胞凋亡测定）以及小鼠肿瘤异种移植物进行了其他实验检查 DUS4L 在 LUAD 进展中的生物学作用。进行RNA测序、蛋白质组分析、质谱分析和免疫共沉淀实验来鉴定和验证DUS4L调节的下游靶基因和信号通路。我们发现DUS4L在LUAD组织中一致上调。体外和体内实验强调了 DUS4L 下调对 LUAD 进展（包括迁移、侵袭和增殖）的抑制作用。从机制上讲，DUS4L被发现与信号分子GRB2相互作用，通过PI3K/AKT和ERK/MAPK途径诱导上皮间质转化（EMT），从而促进LUAD进展和转移。我们的结果确立了DUS4L在驱动进展中的功能作用LUAD 和转移，暗示其作为 LUAD 候选治疗靶点的潜力。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Limited research has focused on the role of dihydrouridine synthases (DUS) family members in human tumors. Our previous findings indicated an impact of dihydrouridine synthase 4 like (DUS4L) on cell proliferation and apoptosis in lung adenocarcinoma (LUAD) A549 cell, yet its broader functions and regulatory mechanisms in LUAD remain elusive.Using a LUAD tissue microarray and immunohistochemical (IHC) staining, we validated variations in DUS4L protein expression levels among LUAD patients and assessed its clinical significance. Additional experiments using short hairpin RNA (shRNA) against DUS4L (sh-DUS4L-2), LUAD cell lines, cell function assays (including wound healing, transwell migration and invasion, colony formation, and apoptosis assays), and mouse tumor xenografts were performed to examine the biological roles of DUS4L in LUAD progression. RNA sequencing, proteomic analyses, mass spectrometry, and co-immunoprecipitation experiments were conducted to identify and validate DUS4L-regulated downstream target genes and signaling pathways.We identified a consistent upregulation of DUS4L in LUAD tissues. In vitro and in vivo experiments underscored the inhibitory effect of DUS4L downregulation on LUAD progression, including migration, invasion, and proliferation. Mechanistically, DUS4L was found to interact with the signaling molecule GRB2, promoting LUAD progression and metastasis by inducing epithelial-mesenchymal transition (EMT) via the PI3K/AKT and ERK/MAPK pathways.Our results establish the functional role of DUS4L in driving the progression and metastasis of LUAD, implicating its potential as a candidate therapeutic target for LUAD.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.