APE1 promotes radiation resistance against radiation-induced pyroptosis by inhibiting the STING pathway in lung adenocarcinoma

Highlights

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  We found that APE1 was significantly upregulated in LUAD tissues compared to the para-carcinoma tissues, and its high expression promoted the proliferation and invasion of the LUAD cells in vitro and in vivo.

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  Mechanistically, APE1 inhibited pyroptosis by inactivating the STING pathway via direct interaction with AIM2 and DDX41.

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  APE1 protects LUAD cells against radiation-induced damage and induces radio-resistance by targeting the STING/DDX41 pathway.

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  APE1 inhibitors should be considered for enhancing the radiosensitivity of LUAD cells and improving patient prognosis and therapeutic outcomes. We believe that the findings of this study are relevant to the scope of your journal and will be of interest to its readership.

Abstract

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.