{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T06:14:36Z","timestamp":1775196876191,"version":"3.50.1"},"reference-count":32,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2023YFF0724501"],"award-info":[{"award-number":["2023YFF0724501"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>The manipulation of host cellular metabolism is a key strategy for flaviviruses like Japanese encephalitis virus (JEV) to establish a productive infection. This study identifies the host NADase CD38 as a central regulator of this process. Using a CRISPR\/Cas9-generated CD38 knockout (KO) TM3 cell model, we found that CD38 deficiency significantly restricted the production of infectious viral particles. While loss of CD38 also partially impaired viral entry, our central finding is that CD38 primarily promotes JEV infection by suppressing a host-intrinsic metabolic defense. We show that CD38 deficiency leads to a surge in intracellular NAD+, which sustains SIRT1 activity and inactivates p53, thereby blocking the mitochondrial apoptosis required for viral propagation. The dominance of this metabolic axis was confirmed through bidirectional pharmacological interventions; while SIRT1 inhibition using EX527 restored JEV replication, SIRT1 activation using SRT1720 suppressed it in wild-type cells. Our work reveals that JEV hijacks the CD38-NAD+-SIRT1-p53 axis to overcome host metabolic defenses in reproductive cell models, establishing CD38 as a promising therapeutic target.<\/jats:p>","DOI":"10.3390\/microorganisms14040796","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T15:14:43Z","timestamp":1775142883000},"page":"796","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Host NADase CD38 Promotes JEV Replication by Targeting the NAD+\/SIRT1 Axis"],"prefix":"10.3390","volume":"14","author":[{"given":"Yuanyuan","family":"Yang","sequence":"first","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruiqin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinran","family":"Li","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinlei","family":"Liu","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Dai","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Gu","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahui","family":"Li","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haodong","family":"Chen","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7791-4167","authenticated-orcid":false,"given":"Rui","family":"Wu","sequence":"additional","affiliation":[{"name":"Research Center for Swine Diseases, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China"},{"name":"Sichuan Science-Observation Experiment Station of Veterinary Drugs and Veterinary Diagnostic Technology, Ministry of Agriculture, Chengdu 611330, China"},{"name":"National Animal Experiments Teaching Demonstration Center, Sichuan Agricultural University, Chengdu 611330, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100994","DOI":"10.1016\/j.mam.2021.100994","article-title":"Pathobiology of Japanese Encephalitis Virus Infection","volume":"81","author":"Sharma","year":"2021","journal-title":"Mol. 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