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Vaccination has reduced both transmission and disease severity. However, emerging viral variants have weakened vaccine effectiveness, highlighting the need for new antiviral therapies. This study examines how the SARS-CoV-2-Spike protein (SARS-2-S) induces the VSIR-ISX signaling pathway, leading to metabolic disturbances that may worsen disease progression. Using RNA sequencing, we found that SARS-2-S expression in pulmonary cells activates genes involved in tryptophan and arachidonic acid (AA) metabolism, altering bioactive mediators like kynurenine and prostanoids, which are crucial for inflammation and immune responses. Mechanistically, the ACE2-MYD88 pathway, activated by SARS-2-S, enhances the VSIR-ISX axis through NF-\u03baB signaling, driving these metabolic disruptions. Chromatin immunoprecipitation and genome sequencing revealed that ISX, activated via VSIR-MAPK signaling, upregulates enzymes involved in AA metabolism by binding directly to their gene promoters. Notably, disrupting the VSIR-ISX axis using shRNA interference or NF-\u03baB inhibitors effectively mitigated these metabolic disturbances. Our findings suggest that the VSIR-ISX pathway could be a promising therapeutic target for treating COVID-19 by addressing virus-induced metabolic disruptions.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s10565-025-10119-2","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T06:27:00Z","timestamp":1766125620000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spike protein\u2013induced VSIR\u2013ISX signaling disrupts metabolic homeostasis and promotes COVID-19\u2013related immune dysfunction"],"prefix":"10.1007","volume":"42","author":[{"given":"Li-Ting","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shen-Nien","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shyh-Shin","family":"Chiou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chee-Yin","family":"Chai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shih-Hsien","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"10119_CR1","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.ejim.2022.06.015","volume":"103","author":"F Angeli","year":"2022","unstructured":"Angeli F, Reboldi G, Trapasso M, Zappa M, Spanevello A, Verdecchia P. 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