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Increased HMGB1 levels in serum\/plasma of COVID\u201019 patients were reported by many studies, which positively correlated with the level of proinflammatory cytokines. Dead cells following SARS\u2010CoV\u20102 infection might release a large amount of HMGB1 and RNA of SARS\u2010CoV\u20102 into extracellular space. HMGB1 is a well\u2010known inflammatory mediator. Additionally, extracellular HMGB1 might interact with SARS\u2010CoV\u20102 RNA because of its high capability to bind with a wide variety of molecules including nucleic acids and could trigger massive proinflammatory immune responses. This review aimed to critically explore the many possible pathways by which HMGB1\u2010SARS\u2010CoV\u20102 RNA complexes mediate proinflammatory responses in COVID\u201019. The contribution of these pathways to impair host immune responses against SARS\u2010CoV\u20102 infection leading to a cytokine storm was also evaluated. Moreover, since blocking the HMGB1\u2010SARS\u2010CoV\u20102 RNA interaction might have therapeutic value, some of the HMGB1 antagonists have been reviewed. The HMGB1\u2010 SARS\u2010CoV\u20102 RNA complexes might trigger endocytosis via RAGE which is linked to lysosomal rupture, PRRs activation, and pyroptotic death. High levels of the proinflammatory cytokines produced might suppress many immune cells leading to uncontrolled viral infection and cell damage with more HMGB1 released. Altogether these mechanisms might initiate a proinflammatory cycle leading to a cytokine storm. HMGB1 antagonists could be considered to give benefit in alleviating cytokine storms and serve as a potential candidate for COVID\u201019 therapy.<\/jats:p>","DOI":"10.1111\/imm.13623","type":"journal-article","created":{"date-parts":[[2022,12,26]],"date-time":"2022-12-26T10:04:23Z","timestamp":1672049063000},"page":"117-131","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["The role of\n                    <scp>HMGB1<\/scp>\n                    in\n                    <scp>COVID\u201019\u2010induced<\/scp>\n                    cytokine storm and its potential therapeutic targets: A review"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3149-5416","authenticated-orcid":false,"given":"Sri","family":"Wulandari","sequence":"first","affiliation":[{"name":"Doctorate Program of Medicine and Health Science, Faculty of Medicine Public Health and Nursing Universitas Gadjah Mada  Yogyakarta Indonesia"},{"name":"Department of Physiology, Faculty of Medicine Universitas Sebelas Maret  Surakarta Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6112-497X","authenticated-orcid":false,"family":"Hartono","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine Universitas Sebelas Maret  Surakarta Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0477-4575","authenticated-orcid":false,"given":"Tri","family":"Wibawa","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine Public Health and Nursing Universitas Gadjah Mada  Yogyakarta Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,1,11]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165878"},{"key":"e_1_2_13_3_1","unstructured":"World Health OrganizationWHO coronavirus (COVID\u201019) dashboard with vaccination data. 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