哺乳动物嘌呤/异嘧啶内切酶1（APE1，APEX1）是一种多功能酶，能维持细胞稳态。它参与碱基切除修复（BER）途径，并在辐射引起的DNA损伤应答中发挥关键作用。然而，APE1驱动的放射抵抗和肺腺癌（LUAD）细胞中焦亡的关系及其潜在分子机制仍不清楚。我们发现相比于癌旁组织，在LUAD组织中APE1显著上调，并在体外和体内促进LUAD细胞的增殖和侵袭。机制上，APE1通过与AIM2和DDX41的直接相互作用，抑制了干扰素基因刺激器（STING）途径，从而抑制焦亡，这些结果经RNA测序和共免疫沉淀实验检测到。APE1通过靶向STING途径保护LUAD细胞免受辐射诱导的损伤并诱导放射抵抗。它能诱导焦亡，并受AIM2和DDX41的负调控。因此，应考虑使用APE1抑制剂来增强LUAD细胞的放射敏感性，提高患者预后和治疗效果。因此，APE1在肿瘤免疫微环境和肿瘤免疫治疗中发挥作用。版权所有 © 2023 Elsevier Inc.

Mammalian apurinic/apyrimidinic endonuclease 1 (APE1, APEX1) is a multifunctional enzyme that maintains cellular homeostasis. It is involved in the base excision repair (BER) pathway and plays a key role in radiation-induced DNA damage response. However, the relationship between APE1-driven radiation resistance and pyroptosis in lung adenocarcinoma (LUAD) cells and the underlying molecular mechanisms remain unclear. We found that APE1 was significantly upregulated in LUAD tissues compared to para-carcinoma tissues and promoted the proliferation and invasion of LUAD cells in vitro and in vivo. Mechanistically, APE1 inhibited pyroptosis by inactivating the interferon gene stimulator (STING) pathway via direct interaction with AIM2 and DDX41, as detected by RNA-seq and co-immunoprecipitation. APE1 protects LUAD cells against radiation-induced damage and induces radio-resistance by targeting the STING pathway. It can induce pyroptosis and is negatively regulated by interactions with AIM2 and DDX41. Therefore, APE1 inhibitors should be considered to enhance the radiosensitivity of LUAD cells and improve patient prognosis and therapeutic outcomes. Thus, APE1 play a role in the tumor immune microenvironment and in tumor immunotherapy.Copyright © 2023. Published by Elsevier Inc.