{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:55:58Z","timestamp":1789480558943,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013014","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T00:00:00Z","timestamp":1744070400000}}],"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T00:00:00Z","timestamp":1743120000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["No. 2021YFC2300800, 2021YFC2300803"],"award-info":[{"award-number":["No. 2021YFC2300800, 2021YFC2300803"]}]},{"name":"National Key Research and Development Program of China","award":["No. 2021YFC2300800, 2021YFC2300803"],"award-info":[{"award-number":["No. 2021YFC2300800, 2021YFC2300803"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31972699, 31725025"],"award-info":[{"award-number":["31972699, 31725025"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Science and Technology Leading Talent Team in Inner Mongolia Autonomous Region","award":["2022LJRC0009"],"award-info":[{"award-number":["2022LJRC0009"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Schistosomiasis affects more than 250 million people worldwide and is one of the neglected tropical diseases. Currently, the treatment of schistosomiasis relies on a single drug-praziquantel-which has led to increasing pressure from drug resistance. Therefore, there is an urgent need to find new treatments. The development of genome sequencing has provided valuable information for understanding the biology of schistosomes. In the genome of <jats:italic>Schistosoma japonicum<\/jats:italic>, approximately 11% of the protein-coding sequences are uncharacterized genes (UGs) annotated as \u201chypothetical protein\u201d or \u201cprotein of unknown function.\u201d These poorly understood genes have been unjustifiably neglected, although some may be essential for the survival of the parasites and serve as potential drug targets. In this study, we systematically mined the highly expressed UGs in both genders of this parasite throughout key developmental stages in their mammalian host, using our previously published <jats:italic>S. japonicum<\/jats:italic> genome and RNA-seq data. By employing <jats:italic>in vitro<\/jats:italic> RNA interference (RNAi), we screened 126 UGs that lack homologs in <jats:italic>Homo sapiens<\/jats:italic> and identified 8 that are essential for the parasite vitality. We further investigated two UGs, <jats:italic>Sjc_0002003<\/jats:italic> and <jats:italic>Sjc_0009272<\/jats:italic>, which resulted in the most severe phenotypes. Fluorescence <jats:italic>in situ<\/jats:italic> hybridization demonstrated that both genes were expressed throughout the body without sex bias. Silencing either <jats:italic>Sjc_0002003<\/jats:italic> or <jats:italic>Sjc_0009272<\/jats:italic> reduced the cell proliferation in the body. Furthermore, <jats:italic>in vivo<\/jats:italic> RNAi indicated both genes are required for the growth and survival of the parasites in the mammalian host. For <jats:italic>Sjc_0002003<\/jats:italic>, we further characterize the underlying molecular cause of the observed phenotype. Through RNA-seq analysis and functional studies, we revealed that silencing <jats:italic>Sjc_0002003<\/jats:italic> reduces the expression of a series of intestinal genes, including <jats:italic>Sjc_0007312<\/jats:italic> (hypothetical protein), <jats:italic>Sjc_0008276<\/jats:italic> (vha-17), <jats:italic>Sjc_0002942<\/jats:italic> (PLA2G15), and <jats:italic>Sjc_0003646<\/jats:italic> (SJCHGC09134 protein), leading to gut dilation. Our work highlights the importance of UGs in schistosomes as promising targets for drug development in the treatment of the schistosomiasis.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013014","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T20:59:02Z","timestamp":1743195542000},"page":"e1013014","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["RNAi screening of uncharacterized genes identifies promising druggable targets in Schistosoma 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