YTHDF2 drives malignant progression in cutaneous melanoma through m⁶A-dependent HMOX1-mediated ferroptosis.

N6-methyladenosine (m6A) modification plays a critical role in eukaryotic mRNA and is significantly associated with cutaneous melanoma. This study investigated the role of the m6A-binding protein YTHDF2 in the pathogenesis of cutaneous melanoma and its potential therapeutic applications. Analyses of public databases indicated that YTHDF2 exhibited elevated expression in various cancers, including cutaneous melanoma, where its levels positively correlated with PD-L1 and negatively correlated with immune and stromal scores. Functionally, the downregulation of YTHDF2 in melanoma cells suppressed proliferation and increased the population of Annexin V/PI--positive cells, an effect that was rescued by the ferroptosis inhibitor, highlighting YTHDF2's involvement in ferroptosis regulation. YTHDF2 knockdown resulted in increased intracellular Fe2+ levels, malondialdehyde, reactive oxygen species, and lipid peroxidation, alongside a reduction in glutathione-effects that were reversed upon ferroptosis inhibition. In vivo studies corroborated the regulatory role of YTHDF2 in ferroptosis. Mechanistically, integrated RNA-seq and RIP-seq analyses demonstrated that YTHDF2 could bind to m6A on HMOX1 transcripts, destabilizing its mRNA and thus regulating HMOX1 expression. Moreover, metformin was shown to inhibit YTHDF2 expression, promoting ferroptosis in melanoma cells. In summary, YTHDF2 modulates ferroptosis in melanoma through the regulation of m6A-dependent HMOX1 mRNA stability, suggesting it as a promising therapeutic target. The capacity of metformin to suppress YTHDF2 indicates its potential utility in hindering melanoma progression.