circSCYL2 antagonizes hnRNPA2B1-mediated m6A-chromatin crosstalk to promote ferroptosis and inhibit metastasis of breast cancer to brain.

Effective options for treating metastasis of breast cancer (BC) to brain remain limited and current therapeutic approaches often show insufficient efficacy. Targeting ferroptosis represents a novel therapeutic oncological strategy, but the role and mechanisms of ferroptosis in BC brain metastasis remain incompletely understood. Here, we observed that circSCYL2 was specifically downregulated in cancer cells from brain metastases. circSCYL2 overexpression inhibited cancer cell metastasis across the blood-brain barrier into the brain. circSCYL2 overexpression also significantly reduced the area of brain metastasis. Transcriptomic sequencing revealed that differentially expressed genes (DEGs) regulated by circSCYL2 were enriched in the ferroptosis signaling pathway. Additionally, circSCYL2 overexpression in brain metastatic cells promoted ferroptosis. Moreover, circSCYL2 upregulated the key ferroptosis molecule ACSL4, while ACSL4 knockdown partially reversed the role of circSCYL2 in promoting ferroptosis. Mechanistically, circSCYL2 competitively binds to the N6-methyladenosine (m6A) reader hnRNPA2B1, impeding its recognition of m6A sites on ACSL4 mRNA. This in turn suppresses hnRNPA2B1-mediated recruitment of SETDB1, thus reducing the H3K9me3 level near the ACSL4 promoter, and enhancing ACSL4 transcription. In conclusion, this study provides the first evidence that circSCYL2 suppresses metastasis of BC to brain by activating ferroptosis through an hnRNPA2B1-dependent m6A-chromatin crosstalk regulatory mechanism. To the best of our knowledge, no previous studies have linked circSCYL2 to ferroptosis or m6A-mediated epigenetic regulation in BC brain metastasis, highlighting the novelty and mechanistic advances provided by our findings. These findings deepen our understanding of BC brain metastasis and identify circSCYL2 as a promising therapeutic target.