{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:09:02Z","timestamp":1785431342404,"version":"3.56.0"},"reference-count":51,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"the Foundation for Innovative Research Groups of the National Natural Science Foundation of China","award":["NSFC82221004 and 82530077"],"award-info":[{"award-number":["NSFC82221004 and 82530077"]}]},{"name":"The CAMS Innovation Fund for Medical Sciences","award":["2025-I2M-XHZY-039, 2024-I2M-007"],"award-info":[{"award-number":["2025-I2M-XHZY-039, 2024-I2M-007"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82472255"],"award-info":[{"award-number":["82472255"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Double Innovation Plan of Jiansu province"},{"name":"Gusu Innovation and Entrepreneurship Leading Talents Program"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2026,5,13]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has profoundly impacted global public health and the economy. Systematic screening of host factors influencing viral infection is critical for understanding virus-host interactions and for developing host-targeted antiviral strategies. Here, we conducted a host cDNA overexpression screen to identify host factors involved in regulating SARS-CoV-2 replication. This approach identified prosaposin (PSAP), a precursor of lysosomal saposin activators (saposin A, B, C, and D), as an efficient host restriction factor that blocks SARS-CoV-2 entry. We demonstrate that PSAP binds with high affinity to the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein. Secreted PSAP efficiently inhibits infection by both SARS-CoV-2 pseudovirus and authentic virus. Mechanistically, PSAP binding facilitates the release of the S1 subunit from the S protein. Molecular docking analysis further revealed that PSAP interacts with the non-receptor-binding motif (non-RBM) region of the domain (RBD). These results suggest that PSAP inhibits SARS-CoV-2 entry through a mechanism analogous to that of neutralizing antibodies. Our findings highlight PSAP as a novel host restriction factor against SARS-CoV-2 infection, offering new insights into potential therapeutic strategies for combating SARS-CoV-2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>The systematic identification of host factors that modulate SARS-CoV-2 infection is critical for elucidating the mechanisms of virus-host interaction and for advancing the development of novel host-directed therapeutic interventions. In this study, we identify the human protein prosaposin (PSAP) as a novel and potent innate restriction factor that effectively blocks SARS-CoV-2 infection. By binding with high affinity to the spike protein\u2019s receptor-binding domain (RBD) at a unique site, PSAP neutralizes the virus, thereby preventing cellular entry. Consequently, this discovery establishes a foundation for a novel host-directed therapeutic strategy. The development of pharmacologic agents that recapitulate PSAP\u2019s action could yield a new class of antivirals that neutralize SARS-CoV-2 by mechanistically disrupting spike protein integrity, offering a complementary approach to conventional antibody therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00129-26","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T13:00:24Z","timestamp":1774530024000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Secretory full-length human prosaposin (PSAP) inhibits SARS-CoV-2 infection through facilitating the release of S1 subunit of spike protein"],"prefix":"10.1128","volume":"17","author":[{"given":"Chongyang","family":"Zhang","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of System Biology of Pathogens and Christophe Merieux Laboratory, National Institute of Pathogen Biology, Chinese 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