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The redox imbalance resulting from oxidative stress is an essential pathogenic mechanism during viral infections. Nevertheless, the regulatory mechanisms of oxidative stress by viral and host factors during SVV infection remain elusive. In this study, we discovered that SVV elicited cellular oxidative stress through the induction of reactive oxygen species production and the suppression of the nuclear factor erythroid 2-related factor 2 (Nrf2)\/heme oxygenase-1 (HO-1) pathway. Our findings indicated that the overexpression of Nrf2\/HO-1 exerted a remarkable anti-SVV effect. Conversely, the inhibition of Nrf2\/HO-1 expression facilitated the proliferation of SVV. HO-1 metabolic products carbon monoxide and biliverdin inhibit SVV replication. HO-1 promotes type I interferon response and interferon-stimulated gene expressions, which contribute to its antiviral mechanism. Furthermore, our findings reveal that the SVV 3C proteinase targets the Nrf2\/HO-1 axis for degradation via caspase pathway, thereby promoting viral replication. Collectively, these results clarify the convoluted molecular mechanisms by which SVV weakens the host\u2019s antioxidant defense system and suggest potential targets for therapeutic interventions regarding SVV infections.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>Nrf2 is a crucial redox regulator responsible for initiating the expression of downstream antioxidant genes, including HO-1 and superoxide dismutase. HO-1, an enzyme induced by stress, performs protective roles through the conversion of heme into carbon monoxide, biliverdin, and iron. Nevertheless, the function of Nrf2\/HO-1 during Seneca Valley virus (SVV) infection is yet to be clearly defined. In this study, we showed that SVV infection led to a reduction in the expression of Nrf2\/HO-1, and the overexpression of Nrf2\/HO-1 induced a potent anti-SVV effect. SVV 3C proteinase promoted the caspase-dependent degradation of Nrf2\/HO-1. As a result, it attenuated the cell's ability to resist oxidative stress and counteracted the antiviral function of Nrf2\/HO-1. Our research further uncovered a novel mechanism through which SVV eludes the host's antiviral effects by disrupting cellular redox balance, offering important targets for preventing and controlling SVV infection.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01656-25","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T14:00:15Z","timestamp":1767621615000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["Seneca Valley virus 3C protease targets the Nrf2\/HO-1 pathway to antagonize its antiviral activity"],"prefix":"10.1128","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9759-8875","authenticated-orcid":true,"given":"Jiangwei","family":"Song","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04trzn023","id-type":"ROR","asserted-by":"publisher"}],"name":"Beijing Key Laboratory for Prevention and Control of Infectious 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