Overcoming oxidative stress is a critical mechanism by which breast cancer cells sustain malignant progression and therapeutic resistance. However, the specific regulatory networks governing this adaptive response remain incompletely understood. Here, we demonstrate that TRIM45, a tumor-suppressive E3 ubiquitin ligase, acts as a key negative regulator of the antioxidant defense system in breast cancer. Clinically, TRIM45 is significantly downregulated in breast cancer tissues, and its low expression strongly correlates with poor patient prognosis. Functionally, ectopic expression of TRIM45 suppresses proliferation, migration, and epithelial-mesenchymal transition (EMT) in MCF-7 and BT549 cells. Mechanistically, we demonstrate that TRIM45 promotes p62 ubiquitination and degradation in breast cancer cells. By promoting the proteasomal degradation of p62, TRIM45 liberates Keap1. This is accompanied by enhanced Nrf2 ubiquitination and restricted nuclear translocation, suggesting a mechanism whereby TRIM45-mediated p62 degradation contributes to Nrf2 pathway suppression.This dismantling of the Keap1/Nrf2 signaling pathway not only suppresses downstream antioxidant targets (HO-1, GPX4) to induce lethal oxidative stress, characterized by elevated ROS and MDA levels alongside reduced GSH and GSH-Px activity, but also attenuates the IGF-1/IGF-1R/ERK signaling pathway. Collectively, our study uncovers a previously unrecognized TRIM45/p62/Keap1/Nrf2 regulatory signaling pathway, establishing TRIM45 as a promising therapeutic target that exploits oxidative vulnerability in breast cancer. Overcoming oxidative stress is a critical adaptive mechanism for breast cancer cells to sustain malignant progression and therapeutic resistance. This study identifies TRIM45, a tumor-suppressive E3 ubiquitin ligase, as a key negative regulator of the antioxidant defense system in breast cancer. Clinically, TRIM45 is significantly downregulated in breast cancer tissues, and its low expression strongly correlates with poor patient prognosis. Functionally, ectopic expression of TRIM45 suppresses proliferation, migration, and epithelial-mesenchymal transition in MCF-7 and BT549 cells. Mechanistically, we demonstrate that TRIM45 directly interacts with p62 and promotes its ubiquitination-dependent proteasomal degradation. Concomitant with p62 reduction, we observed the restoration of Keap1 protein levels, coupled with decreased protein abundance and impaired nuclear translocation of the transcription factor Nrf2. This led to the downregulation of downstream antioxidant genes (HO-1, GPX4) and attenuation of the IGF-1/IGF-1R/ERK signaling pathway. Collectively, these alterations induced lethal oxidative stress, characterized by ROS accumulation and depletion of the glutathione system. Our findings reveal that TRIM45 exerts a tumor-suppressive role in breast cancer by targeting p62 for degradation and thereby disrupting the Keap1/Nrf2 antioxidant axis, nominating TRIM45 as a novel candidate for therapeutic strategies aimed at exploiting oxidative vulnerability.