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Retinoids, vitamin A derivatives, have demonstrated antiviral potential against different viral infections, yet their efficacy against alphaviruses has never been investigated. In this study, tretinoin (TR), or all-trans retinoic acid (ATRA), was evaluated for its anti-CHIKV activity using\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                      models. TR abrogated CHIKV infection efficiently in Vero and C2C12 cells, with a marked reduction (&gt;90%) in viral RNA, proteins, and progeny formation. The IC\n                      <jats:sub>50<\/jats:sub>\n                      of TR against CHIKV was estimated to be 20.05 \u00b5M and 19.71 \u00b5M in Vero and C2C12 cells, respectively. Additionally, TR showed remarkable virucidal activity and effective inhibition during entry, as well as in the early stages of post-CHIKV infection. Next, the global transcriptome profile demonstrated that the \u201csignaling by retinoic acid\u201d pathway was significantly enriched after CHIKV infection, and retinoic acid receptors (RARs), specifically RAR-\u03b2, are the key mediators for the anti-CHIKV effect of TR. Further, the drug alters phosphorylated mitogen-activated protein kinases (MAPKs), NF-\u03baB, and proinflammatory cytokines during CHIKV infection in RAW 264.7 cells. Interestingly, TR protected C57BL\/6 mice from CHIKV challenge by diminishing viral burden, leading to reduced clinical scores and better survival. Similar observations were also noticed in the\n                      <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                      models of CHIKV-infected primary human skeletal muscle myoblasts (HSMMs). In conclusion, this work demonstrated the repurposing potential of TR against CHIKV infection for the first time, encouraging its clinical validation toward future therapeutics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Chikungunya virus (CHIKV) is an arbovirus causing Chikungunya fever (CHIKF), leading to debilitating arthralgia and myalgia. The unavailability of licensed antivirals against CHIKV encourages extensive research to find a therapeutic cure. Retinoids, the derivatives of vitamin A, have been repurposed as antiviral agents against a broad range of viruses; however, their potency against alphaviruses remains unexplored. Accordingly, tretinoin (TR), also known as all-trans retinoic acid (ATRA), was validated for anti-CHIKV efficacy in this investigation. Significant perturbations of CHIKV titer, RNA, and protein levels were observed in the presence of TR following infection, and its antiviral effect was mediated through RAR-\u03b2. Moreover, the anti-CHIKV potential of TR was evaluated in the mouse model and primary human skeletal muscle myoblasts, indicating strong preclinical efficacy. Finally, this is the first study to report the antiviral property of TR against CHIKV infection using\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                      approaches, suggesting its repurposing potential.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00558-26","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T12:54:49Z","timestamp":1791377689000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Repurposing tretinoin, a vitamin A derivative, against Chikungunya virus 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