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Despite the substantial burden on public health, effective therapeutic options for the treatment of RSV infections remain limited. The pathogenesis of RSV is characterized by complex inflammatory responses, while high\u2010mobility group box\u00a01 (HMGB1), a damage\u2010associated molecular pattern protein, is known to play a role in amplifying inflammation. However, the specific role of HMGB1 in RSV infection has not been thoroughly investigated. This study aims to elucidate the role of HMGB1 in RSV replication and to evaluate its potential as a target for antiviral therapy. The interaction between the RSV nucleocapsid (N) protein and HMGB1 was demonstrated through co\u2010immunoprecipitation and mass spectrometry. Knockdown or overexpression of HMGB1 by small interfering RNA or pCMV\u2010HA\u2010HMGB1 resulted in a significant reduction or induction in RSV replication in\u00a0vitro, thereby confirming the critical role of HMGB1 in viral propagation. Moreover, structure\u2010based molecular docking analyses identified glycyrrhizic acid (GA) and amlexanox (AMX) as high\u2010affinity ligands for HMGB1. In cellular studies, both GA and AMX effectively inhibited RSV replication in a dose\u2010dependent manner while selectively suppressing HMGB1's secretion to the cytoplasm or extracellular space from RSV\u2010infected cells. AMX was found to down\u2010regulate HMGB1 expression while GA did not. In experiments using lethal murine RSV infection models, treatment with GA and AMX significantly improved survival rates and reduced lung pathology. In conclusion, these findings suggest that HMGB1 is a promising therapeutic target for RSV infection and highlight GA and AMX as potential antiviral candidates that can modulate HMGB1\u2010mediated immunopathology.<\/jats:p>","DOI":"10.1096\/fj.202600812r","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T09:32:47Z","timestamp":1782466367000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the\n                    <scp>HMGB1<\/scp>\n                    Pathway With Glycyrrhizic Acid and Amlexanox Attenuates\n                    <scp>RSV<\/scp>\n                    \u2010Induced Injury and Viral Propagation"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4634-4711","authenticated-orcid":false,"given":"Pingping","family":"Zhang","sequence":"first","affiliation":[{"name":"Guizhou Key Laboratory of Microbio and Infectious Disease 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