Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination

Abstract

Imatinib (IM) has significantly improved the prognosis of gastrointestinal stromal tumor (GIST) patients, but some patients still have primary resistance to IM, and approximately half of patients develop acquired drug resistance within 2 years of treatment, necessitating exploration of new treatment strategies. Targeting ferroptosis as a novel approach to tumor treatment has gained attention. Yet, there is limited research on ferroptosis in GIST, and the underlying mechanism remains unclear. In this study, we revealed that IM increased lipid reactive oxygen species and intracellular Fe2+ levels, and decreased glutathione levels in GIST. This effect could be partially inhibited by Ferrostatin-1. Additionally, knocking down STUB1 and overexpressing GPX4 reversed the IM-induced ferroptosis effect. Moreover, STUB1 was identified as a novel E3 ubiquitin ligase of GPX4, promoting the ubiquitination at site K191 of GPX4. The combination of the GPX4 inhibitor RSL3 and IM synergistically induces ferroptosis, inhibiting GIST proliferation both in vivo and in vitro. Furthermore, STUB1 and GPX4 expression serve as independent prognostic factors for GIST. In conclusion, This study is the first to demonstrate that IM induces ferroptosis by promoting STUB1-mediated GPX4 ubiquitination in GIST, and the combination of RSL3 and IM emerges as a promising therapeutic strategy for GIST.

Role of Ferroptosis Regulation by Nrf2/NQO1 Pathway in Alcohol-Induced Cardiotoxicity In Vitro and In Vivo

“…GPX4, a selective protein glutathione peroxidase, degrades hydroperoxides and reduces the production of lipid peroxidation that damaged membranes. It also inhibited PUFA-OOH production of PUFA–OH and GSH production of GSSG in cells . The study showed that alcohol significantly reduced GPX4 expression and GSH content.…”

Interplay of Ferroptosis and Cuproptosis in Cancer: Dissecting Metal-Driven Mechanisms for Therapeutic Potentials

“…Regarding breast cancer, doxorubicin-induced cardiotoxicity may involve iron-dependent processes and oxidative stress, prompting co-administration with iron chelators to adjust iron levels and potentially induce ferroptosis [129]. In gastrointestinal stromal tumors, Imatinib has been found to induce ferroptosis through STUB1-mediated GPX4 ubiquitination [130]. In a prior study, we observed that cetuximab, an approved treatment for metastatic CRC with KRAS, enhanced RSL3-induced ferroptosis by suppressing the NRF2/HO-1 pathway in KRAS-mutant CRC [131].…”

Emerging role of glutathione peroxidase 4 in myeloid cell lineage development and acute myeloid leukemia

“…Mechanistically, they demonstrated that STUB1 promoted polyubiquitination of GPX4 on lysine 191, leading to its degradation by the ubiquitin proteasome pathway. They finally showed that the combination of RSL3, a ferroptosis inducer with Imatinib synergistically inhibited GIST cell proliferation [ 47 ].…”