Deferasirox protects against hydrogen peroxide-induced cell apoptosis by inhibiting ubiquitination and degradation of p21WAF1/CIP1

Abstract

Deferasirox (DFX) is an iron chelator approved for the treatment of iron overload diseases. However, the role of DFX in oxidative stress-induced cell apoptosis and the exact molecular mechanisms underlying these processes remain poorly understood and require further investigation. In this study, we found that DFX rendered resistant to H₂O₂-induced apoptosis in HEK293T cells, reduced the intracellular levels of the labile iron pool (LIP) and oxidative stress induced by H₂O₂. Furthermore, DFX inhibited the ubiquitination and degradation of the cyclin-dependent kinase inhibitor p21^WAF1/CIP1 (p21) via modulation of the interaction of p21 with SCF-Skp2. DFX also showed the inhibition effect on the activation of c-Jun N-terminal kinase (JNK), pro-caspase-3 and related mitochondrial apoptosis pathway induced by H₂O₂. These results provide novel insights into the molecular mechanism underpinning iron-mediated oxidative stress and apoptosis, and they may represent a promising target for therapeutic interventions in related pathological conditions.

Keywords: Apoptosis; Deferasirox; Degradation; Labile iron pool; Oxidative stress; p21 (WAF1/CIP1).