DMAMCL induces ferroptosis in neuroblastoma by targeting HMOX1 in MYCN-amplified subtypes whereas targeting STEAP3 in MYCN-nonamplified subtypes.

Abstract

OBJECTIVES: Neuroblastoma (NB) is a common pediatric extracranial solid tumor. Dimethylaminomicheliolide (DMAMCL), a prodrug of Micheliolide (MCL), shows antitumor activity against NB, but its mechanisms remain unclear. This study investigated the antitumor mechanisms of DMAMCL in NB. METHODS: Key pathways/genes were identified by RNA-seq and ferroptosis PCR array. Ferroptosis was confirmed by indicators. Mechanisms were investigated using siRNAs, shRNAs, and overexpression plasmids in vitro and in vivo. Direct targets were screened by LiP-MS. Molecular biology experiments elucidated the mechanisms. RESULTS: DMAMCL induced ferroptosis in NB in vitro and in vivo, upregulating HMOX1. HMOX1 knockdown attenuated DMAMCL-induced ferroptosis and its overexpression triggered ferroptosis in MYCN-amplified NB cells but not in MYCN-nonamplified cells. DMAMCL-induced ferroptosis via HMOX1 upregulation depended on MYCN levels. Mechanistically, DMAMCL bound to KEAP1 in MYCN-amplified NB cells, increasing nuclear NRF2 and upregulating HMOX1. In MYCN-nonamplified NB cells, DMAMCL upregulated STEAP3, increasing Fe2+ and lipid peroxidation to induce ferroptosis. STEAP3 overexpression induced ferroptosis and suppressed tumor growth. DISSCUSION: DMAMCL induces ferroptosis in NB through MYCN-associated dual pathways, activating the NRF2/HMOX1 axis via KEAP1 binding in MYCN-amplified cells, while upregulating STEAP3 in MYCN-nonamplified cells. This provides new insights for DMAMCL application in treating NB subtypes with different MYCN levels.

Key Findings

• DMAMCL induces ferroptosis in neuroblastoma cells both in vitro and in vivo.
• In MYCN-amplified neuroblastoma cells, DMAMCL binds to KEAP1, activates NRF2, and upregulates HMOX1 to trigger ferroptosis.
• In MYCN-nonamplified neuroblastoma cells, DMAMCL induces ferroptosis by upregulating STEAP3, which increases Fe2+ and lipid peroxidation.

Clinical Significance

Citation

Ma Yifan, Zhang Simeng, Zhang Dongyanget al.. DMAMCL induces ferroptosis in neuroblastoma by targeting HMOX1 in MYCN-amplified subtypes whereas targeting STEAP3 in MYCN-nonamplified subtypes. Redox report : communications in free radical research. 2026-Dec-31.