Pharmacological targeting of FKBPL with rapamycin sensitizes triple-negative breast cancer to ferroptosis.

Abstract

Triple-negative breast cancer (TNBC) remains a clinically formidable subtype, while resistant to conventional apoptotic cell death pathways, it exhibits a unique and exploitable vulnerability to ferroptosis. Here, we identify the FK506-binding protein-like (FKBPL) as a novel scaffold that dictates ferroptosis sensitivity and promotes TNBC progression. Bioinformatic and clinical analyses revealed that FKBPL was significantly overexpressed in TNBC and correlated with inferior patient prognosis. Functional characterization demonstrated that FKBPL knockdown markedly impaired TNBC cell proliferation and migration in vitro and suppressed tumor growth in vivo. Mechanistically, FKBPL modulated the kelch-like ECH associated protein 1 (KEAP1)-associated ubiquitination and increased nuclear factor erythroid-related factor 2 (NRF2) protein abundance, reinforcing cellular antioxidant defenses and reducing ferroptosis sensitivity. Notably, the clinically approved agent rapamycin was found to directly bind to FKBPL, inducing its proteasomal degradation and significantly sensitizing TNBC cells to ferroptosis. Given the emerging links between ferroptosis and immunogenicity, single-cell transcriptomic analysis further illustrated that FKBPL+ malignant cells are predicted to interact with neighboring immune compartments, suggesting a potential association with microenvironmental remodeling within the TNBC microenvironment. Collectively, this study identifies FKBPL as a pivotal regulatory node connecting protein homeostasis with ferroptosis and provides a mechanistic rationale for repurposing rapamycin to therapeutically target the inherent ferroptotic vulnerability of TNBC.

Key Findings

• FKBPL is overexpressed in triple-negative breast cancer (TNBC) and correlates with poor patient prognosis.
• FKBPL promotes TNBC progression by modulating KEAP1-associated ubiquitination and increasing NRF2 protein levels, enhancing antioxidant defenses and reducing ferroptosis sensitivity.
• Rapamycin binds to FKBPL, induces its proteasomal degradation, and sensitizes TNBC cells to ferroptosis, suggesting a therapeutic strategy to exploit ferroptotic vulnerability in TNBC.

Clinical Significance

Citation

Li Rongxue, Ke Hang, Chen Zihanet al.. Pharmacological targeting of FKBPL with rapamycin sensitizes triple-negative breast cancer to ferroptosis. International journal of biological macromolecules. 2026-Oct-16.