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

At present, effective treatment options for breast cancer (BC) brain metastasis remain limited, and current therapeutic approaches often show insufficient efficacy. Targeting ferroptosis represents a novel therapeutic strategy in the field of oncology. However, the role and mechanisms of ferroptosis in BC brain metastasis are not fully understood. Here, we observed that circSCYL2 was specifically down-regulated in cancer cells originating from brain metastases. Overexpression of circSCYL2 inhibited the metastasis of cancer cells across the blood-brain barrier to the brain. circSCYL2 overexpression significantly reduced the area of brain metastasis. Transcriptome sequencing revealed that differentially expressed genes (DEGs) regulated by circSCYL2 were enriched in the ferroptosis signaling pathway. Overexpression of circSCYL2 in brain metastatic cells promotes ferroptosis. Moreover, circSCYL2 upregulated the key ferroptosis molecule ACSL4. Knockdown of ACSL4 partially reversed the promotive role of circSCYL2 on ferroptosis. Mechanistically, circSCYL2 competitively bound to the N6-methyladenosine (m6A) reader hnRNPA2B1, impeding its recognition of m6A sites on ACSL4 RNA, which in turn suppresses hnRNPA2B1-mediated recruitment of SETDB1, reduces H3K9me3 level near the ACSL4 promoter, and enhances ACSL4 transcriptional expression. In conclusion, this study provides the first evidence that circSCYL2 suppresses BC brain metastasis by activating ferroptosis through an hnRNPA2B1-dependent m6A regulatory mechanism. No prior studies have linked circSCYL2 to ferroptosis or m6A-mediated epigenetic regulation in BC brain metastasis, highlighting the novelty and mechanistic advancement of our findings. These findings advance current understanding of BC brain metastasis and identify circSCYL2 as a promising therapeutic target.