RBM15B-driven m6A hypomethylation destabilizes lncRNA SCAMP1 and trophoblast function in unexplained recurrent miscarriage

Abstract Background Recurrent spontaneous abortion (RSA) affects numerous women worldwide, with a significant proportion categorized as unexplained recurrent spontaneous abortion (URSA). Recent evidence suggests that N6-methyladenosine (m6A) methylation, a critical post-transcriptional modification influencing RNA stability and function, plays a key role in URSA pathogenesis. Notably, long non-coding RNAs (lncRNAs) are key targets of m6A modification, and their dysregulation contributes to trophoblast dysfunction—a core pathological feature of URSA. However, the m6A-mediated regulatory mechanisms of lncRNAs in URSA remain unclear. Results Global m6A levels were significantly reduced in URSA villous tissues, accompanied by downregulated expression of m6A methyltransferase RBM15B and lncRNA SCAMP1. SCAMP1 was confirmed to undergo m6A modification, and its hypomethylation in URSA decreased its stability. Functional assays showed that SCAMP1 knockdown impaired HTR-8/SVneo cell proliferation, migration, and invasion, while RBM15B regulated SCAMP1 expression via m6A methylation. Further, SCAMP1 interacted with m6A reader IGF2BP2 to regulate LIN28B mRNA stability. Silencing SCAMP1 or IGF2BP2 reduced LIN28B expression, and LIN28B overexpression partially rescued trophoblast function. Collectively, the RBM15B-SCAMP1-LIN28B axis was found to regulate trophoblast function. Conclusions Reduced m6A methylation in URSA tissues, associated with RBM15B downregulation, destabilizes lncRNA SCAMP1 and impairs trophoblast function via the IGF2BP2-LIN28B pathway. The RBM15B/SCAMP1/ IGF2BP2/LIN28B axis provides novel insights into URSA pathogenesis and suggests potential therapeutic targets.