RSL3 Promotes STAT3 Ubiquitination to Induce Autophagy and Apoptosis in PARPi-Resistant Breast Cancer Cells

Background: Breast Cancer remains the most common malignancy among women worldwide. Current systemic treatment strategies include chemotherapy, immunotherapy, bone-stabilizing agents, endocrine therapy for hormone receptor-positive disease, anti-HER2 therapy for HER2-positive disease, and poly (ADP-ribose) polymerase (PARP) inhibitors for BRCA mutation cases. However, effectively overcoming drug resistance and reducing recurrence and metastasis rates remain major therapeutic challenges.

Methods: To investigate the underlying mechanism of RSL3 in PARPi-resistant breast Cancer cells, we treated several PARPi-resistant breast Cancer cells with varying doses of RSL3. The regulatory proteins of STAT3 were analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Immunoprecipitation and ubiquitination assay were performed to identify the STAT3 ubiquitination levels.

Results: Recently, we identified that RSL3, a Ferroptosis Activator, exhibits potent antitumor activity against PARPi-resistant breast Cancer. Yet, its underlying mechanism remains unclear. Here, we demonstrate that RSL3 directly targets STAT3 and promotes its degradation via the ubiquitination pathway, leading to increased LC3-II levels and decreased p62 expression. These changes ultimately enhance Autophagy, which at least partially contributes to elevated Apoptosis. Rescue experiments confirmed that STAT3 overexpression reverses RSL3-induced Autophagy and Apoptosis.

Conclusions: Our findings highlight RSL3 as a promising therapeutic agent and STAT3 as a potential target for treating PARPi-resistant breast Cancer.

PARPi-resistant breast cancer; RSL3; STAT3; apoptosis; ubiquitination.