N⁶-Methyladenosine on Key Messenger RNAs Governs Reproductive Development and Metabolic Adaptation in Human Blood...

Schistosomiasis, a neglected tropical disease, affects more than 250 million people worldwide. The pathology and transmission of schistosomiasis rely on the parasite's extended survival and massive egg output. While N⁶-methyladenosine (m⁶A) messenger RNA modification is an important epigenetic regulator, its functional roles in pathogenic helminths remain entirely unexplored. Here, we comprehensively characterize the m⁶A landscape in the human blood fluke Schistosoma japonicum. We generated high-resolution transcriptome-wide m⁶A maps for adult male and female parasites, revealing distinct sex-specific methylation patterns. Functional investigation of the conserved m⁶A writer complex demonstrated that m⁶A methyltransferase-like-3/14 (METTL3/14)-mediated methylation is indispensable for female reproductive development and oviposition. In males, m⁶A modification is essential for maintaining tegumental integrity, metabolic homeostasis, and motility. Mechanistically, integrated methylated RNA immunoprecipitation sequencing and RNA sequencing analyses following METTL3 knockdown identified key m⁶A-modified transcripts, including glutamine synthetase, which underpin the observed phenotypic defects. Our study provides the first functional evidence of m⁶A-mediated epitranscriptomic regulation in a parasitic helminth, establishing it as a master regulator of reproductive and somatic development and revealing the m⁶A pathway as a potentially important target for developing novel strategies against schistosomiasis.