耐药是食管腺癌（ESCC）中的一个重要临床问题，同时迫切需要寻找新的治疗靶点。二肽基肽酶III（DPP3）是一种锌依赖性氨肽酶，参与蛋白质降解的末期阶段。许多研究已经报道了DPP3在多种恶性肿瘤中的过表达和致癌功能。本研究旨在确定DPP3在ESCC中的表达模式和功能角色。使用qRT-PCR评估了正常和肿瘤组织中的DPP3表达，并与GEO和TCGA的ESCC基因表达数据集进行了证实。通过shRNA在ESCC细胞中进行了DPP3稳定沉默，并评估了其对细胞增殖、迁移、细胞周期、凋亡以及核因子红细胞2相关因子2（NRF2）通路的激活的影响。结果表明，DPP3沉默导致ESCC细胞的增殖减少、凋亡增加和迁移抑制。此外，DPP3沉默导致NRF2通路蛋白（如NRF2、G6PD和NQO1）的下调，以及对氧化应激诱导的细胞死亡和化疗的增加敏感性。综上所述，这些结果表明DPP3在ESCC中起着关键作用，DPP3/NRF2轴可能成为针对这种恶性肿瘤的抗化疗耐药性的有吸引力的治疗靶点。版权所有2023年作者。

Resistance to therapy in (ESCC) is a critical clinical problem and the identification of novel therapeutic targets is highly warranted. Dipeptidyl peptidase III (DPP3) is a zinc-dependent aminopeptidase and functions in the terminal stages of protein turnover. Several studies have reported overexpression and oncogenic functions of DPP3 in numerous malignancies. This study aimed to determine the expression pattern and functional role of DPP3 in ESCC. DPP3 expression was assessed in normal and tumor tissues using qRT-PCR and corroborated with ESCC gene expression datasets from GEO and TCGA. DPP3 stable knockdown was performed in ESCC cells by shRNA and its effect on cell proliferation, migration, cell cycle, apoptosis, and activation of nuclear factor erythroid 2- related factor 2 (NRF2) pathway was assessed. The results suggested that DPP3 knockdown lead to reduced proliferation, increased apoptosis, and inhibited migration of ESCC cells. Additionally, DPP3 knockdown led to downregulation of the NRF2 pathway proteins, such as NRF2, G6PD, and NQO1 along with increased sensitivity towards oxidative stress-induced cell death and chemotherapy. Conclusively, these results demonstrate critical role of DPP3 in ESCC and DPP3/NRF2 axis may serve as an attractive therapeutic target against chemoresistance in this malignancy.Copyright 2023 The Author(s).