TRIM38 Suppresses Breast Cancer Progression via Modulating SQSTM1 Ubiquitination and Autophagic Flux

Abstract TRIM38, an E3 ubiquitin‐protein ligase, has previously been implicated in innate immune and inflammatory responses, yet its role in breast cancer regulation remains unclear. This study elucidates the suppressive function of TRIM38 in breast cancer progression. The results indicate a decreased expression of TRIM38 in breast cancer tissues compared to adjacent non‐cancerous counterparts, and its reduced expression correlates with unfavorable clinical outcomes in breast cancer patients. Both in vitro and in vivo experiments demonstrate that TRIM38 inhibits breast cancer proliferation, migration, and invasion. Furthermore, an inverse regulatory relationship between TRIM38 protein level and autophagic flux is observed. Mechanistically, SQSTM1/p62 is identified as a novel substrate of TRIM38, which promotes non‐degradative K63‐linked ubiquitination at SQSTM1 K420 residue. This kind of ubiquitination disrupts the interaction between SQSTM1 and LC3, thereby impeding autophagic flux. Collectively, the findings underscore TRIM38 as a crucial regulator of autophagy and present novel, promising therapeutic targets for breast cancer.