胸腺嘧啶酸合成酶（TYMS）参与多种癌症的恶性过程，并作为癌症治疗靶点受到广泛关注。然而，食管鳞状细胞癌（ESCC）的致癌机制报道较少。本研究旨在阐明TYMS在ESCC中的生物学作用和致癌机制，并探讨将TYMS作为肿瘤标记物用于诊断和ESCC治疗的药物靶点的可能性。使用慢病毒转导建立了稳定过表达TYMS的细胞，用于细胞增殖的分析。通过RNA测序探索可能的致癌机制。GEPIA数据库分析显示，食管癌组织中TYMS的表达高于正常组织。MTT实验、克隆形成实验和裸鼠皮下肿瘤模型发现，过表达TYMS增加了细胞增殖。转录组测序分析揭示，TYMS过表达ESCC细胞中促进的细胞增殖是通过激活核因子红细胞相关因子2（Nrf2）基因表达和Nrf2依赖抗氧化酶来缓解氧化应激，这由谷胱甘肽（GSH），谷胱甘肽过氧化物酶（GPX）活性的增加和活性氧的减少所证实。在TYMS过表达细胞中使用Nrf2活性抑制剂（ML385）抑制了Nrf2依赖性抗氧化酶基因的表达，从而增加氧化应激并阻断细胞增殖。 我们的研究表明，TYMS通过激活Nrf2和Nrf2依赖的抗氧化酶基因的表达，通过缓解氧化应激在ESCC的细胞增殖中发挥了新颖且有效的调控作用。这些特性使TYMS和Nrf2成为ESCC临床化疗的有吸引力的靶点。 版权：© 2023杨等。本文是一篇开放获取文章，根据知识共享署名许可发布，允许在任何媒体中进行无限制使用、分发和复制，前提是保留原作者和来源的原始归属。

Thymidylate synthase (TYMS) is involved in the malignant process of multiple cancers, and has gained much attention as a cancer treatment target. However, the mechanism in carcinogenesis of esophageal squamous cell cancer (ESCC) is little reported. The present study was to clear the biological roles and carcinogenic mechanism of TYMS in ESCC, and explored the possibility to use TYMS as a tumor marker in diagnosis and a drug target for the treatment of ESCC.Stably TYMS-overexpression cells established by lentivirus transduction were used for the analysis of cell proliferation. RNA sequencing was performed to explore the possible carcinogenic mechanisms.GEPIA databases analysis showed that TYMS expression in esophageal cancer tissues was higher than that in normal tissues. The MTT assay, colony formation assay, and nude mouse subcutaneous tumor model found that the overexpression of TYMS increased cell proliferation. Transcriptome sequencing analysis revealed that the promoted cell proliferation in TYMS-overexpression ESCC cells were mediated through activating genes expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2 dependent antioxidant enzymes to relieve oxidative stress, which was confirmed by increased glutathione (GSH), glutathione peroxidase (GPX) activities, and reduced reactive oxygen species. Nrf2 active inhibitors (ML385) used in TYMS-overexpression cells inhibited the expression of Nrf2-dependent antioxidant enzyme genes, thereby increasing oxidative stress and blocking cell proliferation.Our study indicated a novel and effective regulatory capacity of TYMS in the cell proliferation of ESCC by relieving oxidative stress through activating expression of Nrf2 and Nrf2-dependent antioxidant enzymes genes. These properties make TYMS and Nrf2 as appealing targets for ESCC clinical chemotherapy.Copyright: © 2023 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.