CIRBP Stabilizes Slc7a11 mRNA to Sustain the SLC7A11/GPX4 Antioxidant Axis and Limit Ferroptosis in Doxorubicin-Induced Cardiotoxicity

Abstract

Doxorubicin-induced cardiotoxicity (DIC) significantly constrains the clinical efficacy of anthracycline chemotherapy, primarily through the induction of ferroptosis, an iron-dependent, regulated cell death driven by oxidative stress and lipid peroxidation. However, the upstream regulators of ferroptosis in DIC remain incompletely defined. Cold-inducible RNA-binding protein (CIRBP) exhibits cardioprotective effects in various pathological contexts, but its precise role in ferroptosis-related cardiotoxicity is unknown. This study investigated whether CIRBP mitigates DIC by modulating the ferroptosis pathway via the SLC7A11 (Solute carrier family 7 member 11)/GPX4 (Glutathione peroxidase 4) axis. We observed marked downregulation of CIRBP in cardiac tissues and cardiomyocytes following doxorubicin exposure. CIRBP knockout significantly exacerbated cardiac dysfunction, mitochondrial damage, oxidative stress, and lipid peroxidation, accompanied by increased mortality rates. Conversely, CIRBP overexpression alleviated these pathological changes. Molecular docking and dynamics simulations, supported by transcriptomic analyses, revealed direct binding of CIRBP to the 3′-UTR of Slc7a11 mRNA, enhancing its stability and promoting translation. Correspondingly, CIRBP deficiency markedly suppressed SLC7A11 and GPX4 expression, impairing cystine uptake, glutathione synthesis, and antioxidant defenses, thus amplifying ferroptosis. These ferroptotic alterations were partially reversed by ferroptosis inhibitor ferrostatin-1 (Fer-1). Collectively, this study identifies CIRBP as a critical regulator of ferroptosis in DIC, elucidating a novel post-transcriptional mechanism involving Slc7a11 mRNA stabilization. These findings offer new insights into ferroptosis regulation and highlight CIRBP as a potential therapeutic target for preventing anthracycline-associated cardiac injury.