TRAF3IP3 Induces ER Stress‐Mediated Apoptosis with Protective Autophagy to Inhibit Lung Adenocarcinoma Proliferation

Abstract TNF receptor‐associated factor 3 interacting protein 3 (TRAF3IP3/T3JAM) exhibits dual roles in cancer progression. While upregulated in most malignancies and critical for immune regulation. However, the specific effects and molecular mechanisms of TRAF3IP3 on the progression of lung adenocarcinoma (LUAD) remains poorly understood. This study reveals TRAF3IP3 is upregulated in several tumor tissues but exclusively decreased in LUAD and Lung squamous cell carcinoma (LUSC) tissues, consequential in a favorable overall survival (OS) in LUAD rather than LUSC. Herein, it is reported that TRAF3IP3 can suppress cell proliferation and promote the apoptosis rate of LUAD cells by inducing excessive ER stress‐related apoptosis. Importantly, TRAF3IP3 triggers ER stress via the PERK/ATF4/CHOP pathway, accompanied by stimulated ER stress‐induced cytoprotective autophagy in LUAD cells. Through IP‐MS analysis, STRN3 is identified as a direct downstream interactor with TRAF3IP3 and corroborated to regulate ER stress positively. Mechanistically, TRAF3IP3 facilitates the recruitment of STRN3 to the ER lumen through its transmembrane domain and fulfills its functional role in ER stress in an STRN3‐dependent manner in LUAD cells. Given its dual role in orchestrating ER stress‐associated apoptosis and autophagy in LUAD cell fate determination, the importance of TRAF3IP3 is highlighted as novel therapeutic target for LUAD treatment.