Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma

TLDR

High‑risk neuroblastoma is a devastating malignancy with very limited therapeutic options, and noncanonical ferroptosis induction involves increased intracellular labile Fe(II) via heme oxygenase‑1 activation sufficient to trigger ferroptosis. The study identifies withaferin A as a natural ferroptosis‑inducing agent in neuroblastoma that operates via a novel double‑edged mechanism. WA dose‑dependently activates NRF2 through targeting Kelch‑like ECH‑associated protein 1 to induce noncanonical ferroptosis or inhibits GPX4 to trigger canonical ferroptosis. The double‑edged mechanism explains WA’s superior efficacy over etoposide or cisplatin in killing diverse high‑risk neuroblastoma cells, suppressing xenograft growth and relapse, and nano‑targeting enables systemic delivery with enhanced tumor accumulation, supporting a novel ferroptosis‑based therapeutic strategy.

Abstract

High-risk neuroblastoma is a devastating malignancy with very limited therapeutic options. Here, we identify withaferin A (WA) as a natural ferroptosis-inducing agent in neuroblastoma, which acts through a novel double-edged mechanism. WA dose-dependently either activates the nuclear factor–like 2 pathway through targeting of Kelch-like ECH-associated protein 1 (noncanonical ferroptosis induction) or inactivates glutathione peroxidase 4 (canonical ferroptosis induction). Noncanonical ferroptosis induction is characterized by an increase in intracellular labile Fe(II) upon excessive activation of heme oxygenase-1, which is sufficient to induce ferroptosis. This double-edged mechanism might explain the superior efficacy of WA as compared with etoposide or cisplatin in killing a heterogeneous panel of high-risk neuroblastoma cells, and in suppressing the growth and relapse rate of neuroblastoma xenografts. Nano-targeting of WA allows systemic application and suppressed tumor growth due to an enhanced accumulation at the tumor site. Collectively, our data propose a novel therapeutic strategy to efficiently kill cancer cells by ferroptosis.