Clinical evidence demonstrates that induction differentiation therapy is a useful treatment strategy for melanoma. Circular RNAs (circRNAs) plays a crucial role in melanoma cell proliferation, resistance and metastasis. However, the roles of circRNAs during melanoma cell differentiation have not been fully investigated. This study aimed to investigate the role and mechanism of circSipa1l1 in melanoma cell differentiation.All-trans-retinoic acid (ATRA) or sodium phenylbutyrate-4 (PB-4) were employed to induce melanoma B16 cells differentiation, and whole transcriptome sequencing was performed to screen for differentially expressed circRNAs. RNA stability assay, quantitative real-time polymerase chain reaction (qRT-PCR), tissue microarray and fluorescence in situ hybridization (FISH) was employed to confirm the existence, expression level and subcellular localization of circSipa1l1. Cell counting kit-8 (CCK-8), colony formation, cell cycle analysis, melanin content, tyrosinase activity assay, RNA pull-down, RNA immunoprecipitation (RIP) and western blotting were used to evaluate the effect of circSipa1l1 on melanoma cell differentiation and explore its regulatory mechanism. Finally, mouse xenograft models were used to assess the effect of circSipa1l1 silencing on tumor growth in vivo.CircSipa1l1 was significantly downregulated in ATRA- or PB-4-treated B16 cells and highly expressed in melanoma patient tissues. Silencing circSipa1l1 induced cell-cycle arrest and differentiation in melanoma A375 and B16 cells, while its overexpression promoted proliferation. Mechanistically, circSipa1l1 directly interacts with insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), a key RNA-binding protein. Silencing circSipa1l1 inhibited the IGF2BP1 and rho GDP-dissociation inhibitor 2 (ARHGDIB) mRNA interaction, destabilizing ARHGDIB mRNA and subsequently inhibiting the extracellular signal-regulated kinase (ERK) signaling pathway-ultimately inducing differentiation and repressing cell cycle progression. Furthermore, silencing circSipa1l1 significantly inhibited tumor growth in both B16 and A375 xenograft models.Our findings reveal that circSipa1l1 acts as an oncogenic circRNA by regulating the IGF2BP1/ARHGDIB/ERK axis in melanoma, suggesting it could be a potential therapeutic target for melanoma differentiation therapy.© 2025. The Author(s).