Artesunate induces ferroptosis in gastric cancer by targeting the TFRC-HSPA9 axis for iron homeostasis regulation

Ferroptosis, a recently characterized form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a promising therapeutic strategy for cancer treatment due to its potential for selectively targeting cancer cells. Exploiting FDA-approved drugs to induce ferroptosis offers a novel approach that exploits cancer cells' vulnerabilities in iron metabolism and oxidative stress. Here, we identify artesunate, an antimalarial drug, as a potent inducer of ferroptosis in gastric cancer cells and reveal the transferrin receptor (TFRC) as a key mediator in this process. Notably, our study is the first to demonstrate an interaction between artesunate and TFRC through molecular docking and surface plasmon resonance (SPR) experiments, highlighting a novel mechanism by which artesunate stabilizes TFRC by inhibiting its lysosomal degradation. This stabilization is regulated via the heat shock protein HSPA9, another previously unreported interaction. Disrupting the TFRC-HSPA9 interaction facilitates iron accumulation and lipid peroxidation, hallmark features of ferroptosis, leading to significant cancer cell death. Additionally, in vivo studies confirm artesunate's anti-tumor efficacy, showing marked tumor growth inhibition and minimal systemic toxicity. These findings underscore the therapeutic relevance of targeting ferroptosis in cancer, particularly by leveraging TFRC's role in iron homeostasis. Furthermore, this study expands the understanding of post-translational regulation in ferroptosis, offering a new perspective on the role of artesunate in cancer therapy.