{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T19:11:50Z","timestamp":1787771510111,"version":"build-2784847793"},"reference-count":57,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Jiangsu Distinguished Professor Program","award":["804139"],"award-info":[{"award-number":["804139"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2026,8,18]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The persistent threat of porcine epidemic diarrhea virus (PEDV) to the global swine industry is compounded by high neonatal piglet mortality and the absence of effective antiviral therapies. Host-directed strategies that reinforce immunity offer a promising avenue to counter viral immune evasion. Through screening of an FDA-approved compound library, we identify the small-molecule cyclocytidine hydrochloride (Cyclo-C) as a potent inhibitor of PEDV replication that acts by stabilizing the peroxisomal biogenesis factor PEX13, a previously unrecognized host restriction factor. The antiviral activity of Cyclo-C is strictly PEX13-dependent, as it is completely abrogated in PEX13 knockout cells. Mechanistically, Cyclo-C disrupts the interaction between PEX13 and the viral nonstructural protein 8 (NSP8), thereby preventing NSP8-mediated PEX13 degradation and the subsequent induction of PI3K\/AKT\/mTOR-driven pexophagy. Preservation of peroxisomal integrity stabilizes the peroxisome-localized pool of MAVS, leading to a robust enhancement of type III interferon (IFN-III) responses that suppress viral replication. Critically, this mechanism translates\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      , where Cyclo-C treatment of PEDV-challenged piglets significantly reduces mortality, lowers viral loads, and protects intestinal villus architecture. Our findings establish Cyclo-C as a first-in-class host-directed therapeutic candidate and validate the concept that pharmacological preservation of peroxisome-mediated innate immunity represents an effective antiviral strategy against enteric coronaviruses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>The high genetic variability of porcine epidemic diarrhea virus (PEDV) limits current vaccine efficacy, and no antiviral therapeutics exist. Host-directed therapies targeting cellular pathways that viruses exploit for immune evasion offer an alternative approach. Here, we identify the FDA-approved compound Cyclo-C as a potent inhibitor of PEDV replication. Cyclo-C acts by stabilizing PEX13, a host protein that the virus degrades to evade immunity. By blocking viral protein NSP8 from binding PEX13, Cyclo-C prevents virus-induced pexophagy, thereby preserving peroxisomal integrity. This preserves peroxisome-localized MAVS and enhances type III interferon responses. In infected neonatal piglets, Cyclo-C reduced mortality and viral loads while protecting intestinal integrity. This study provides proof of concept that targeting peroxisomal immune regulation is a viable antiviral strategy and identifies Cyclo-C as a promising candidate for treating PEDV infection.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00785-26","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T13:01:38Z","timestamp":1784293298000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Cyclo-C stabilizes PEX13 to inhibit porcine epidemic diarrhea virus replication by blocking pexophagy-mediated disruption of antiviral innate immunity"],"prefix":"10.1128","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7023-5755","authenticated-orcid":true,"given":"Jinxiu","family":"Lou","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05td3s095","id-type":"ROR","asserted-by":"publisher"}],"name":"Key Laboratory of Animal Disease Diagnostics 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