Effects of Isorhapontigenin on Cell Viability, Colony‐Forming Efficiency, and Ferroptosis via Methyltransferase‐Like 14‐Mediated m ⁶ A Modification of Solute Carrier Family 7 Member 11 in Human Epidermal Growth Factor Receptor 2‐Enriched a

ABSTRACT As a key regulator of N 6 ‐methyladenosine (m 6 A) modification, methyltransferase‐like 14 (METTL14) has been implicated in the progression of various cancers; however, its functional role in breast cancer remains controversial. Isorhapontigenin (ISO), a natural polyphenolic compound, has been identified as a METTL14 agonist with antitumor potential in multiple malignancies. Nevertheless, the biological function of ISO in breast cancer, particularly its mechanism of regulating METTL14 and downstream signaling pathways, has not been fully elucidated. This study aimed to explore the effects of ISO on breast cancer cell viability, colony‐forming efficiency, and ferroptosis and investigate whether ISO exerts these effects by regulating METTL14 expression. Bioinformatics analyses were performed to identify differentially expressed m 6 A‐related genes in breast cancer tissues. CCK‐8 and colony formation assays were used to evaluate the effects of ISO on breast cancer cell viability and colony‐forming efficiency. Ferroptosis was assessed by quantifying ferroptosis‐related indicators, including reactive oxygen species, glutathione, malondialdehyde, and intracellular Fe 2+ levels. METTL14‐overexpressing cell lines, as well as METTL14‐ and SLC7A11‐silenced cell lines, were constructed to explore gene functions. Bioinformatics analysis revealed that METTL14 is downregulated in basal‐like and HER2‐enriched breast cancer subtypes, and METTL14 overexpression suppressed cell viability and colony‐forming efficiency and promoted ferroptosis in these METTL14‐low subtypes. ISO also suppressed cell viability and colony‐forming efficiency and induced ferroptosis in these cell subtypes. Mechanistically, ISO exerted its effects by upregulating METTL14 expression, which in turn induced m 6 A modification of SLC7A11 mRNA. In conclusion, ISO reduced cell viability and colony‐forming efficiency, and promoted ferroptosis in HER2‐enriched and basal‐like breast cancer cells through promoting METTL14‐dependent m 6 A modification of SLC7A11 mRNA. These findings suggest that ISO may serve as a candidate therapeutic agent for the treatment of HER2‐enriched and basal‐like breast cancer.