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It is not identified whether high\u2010mobility group box 1 (HMGB1), a representative damage\u2010associated molecular pattern (DAMP) molecule, could influence mitochondrial dynamics in endothelial cells. The objective of this study is to clarify the effect of HMGB1 on mitochondrial dynamics in endothelial cells and the underlying mechanism. EA.hy926 human endothelial cells were incubated with recombinant HMGB1 (rHMGB1); mitochondrial morphology was observed with a confocal microscope and transmission electron microscope (TEM). The expression of dynamin\u2010related protein 1 (Drp1), Mitofusin 1 (Mfn1), Mitofusin 2 (Mfn2), Optic atrophy 1 (Opa1), phosphatase and tensin homolog\u2010 (PTEN\u2010) induced kinase 1 (PINK1), NOD\u2010like receptor 3 (NLRP3), caspase 1, cleaved caspase 1, 20S proteasome subunit beta 5 (PSMB5), and antioxidative master nuclear factor E2\u2010related factor 2 (NRF2) and the concentration of interleukin 1<jats:italic>\u03b2<\/jats:italic> (IL\u20101<jats:italic>\u03b2<\/jats:italic>) were determined. Specific inhibitors C29, TAK\u2010242, FPS\u2010ZM1, AMD3100, and epoxomicin were used to block toll\u2010like receptor 2 (TLR2), toll\u2010like receptor 4 (TLR4), receptor for advanced glycation end products (RAGE), C\u2010X\u2010C\u2010chemokine receptor 4 (CXCR4), and PSMB5, respectively. siRNAs were used to silence the expression of NRF2. rHMGB1 promoted mitochondrial fusion in endothelial cells, while no significant proinflammatory effects were found. The expression of mitochondrial fission protein Drp1 and phosphorylated subtypes p\u2010Drp1\u2010S616 and p\u2010Drp1\u2010S637 were all downregulated; no significant expression changes of PINK1 and Mfn1, Mfn2, and Opa1 were found. Inhibition of CXCR4 but not TLR4, RAGE, or TLR2 reversed rHMGB1\u2010induced Drp1 downregulation and mitochondrial fusion. Interestingly, inhibition of TLR4 with TAK\u2010242 promoted Drp1 downregulation and mitochondrial fusion. rHMGB1 increased the expression of NRF2 and PSMB5; inhibition of PSMB5 but not silencing NRF2 abolished rHMGB1\u2010induced Drp1 downregulation and mitochondrial fusion. These results indicate that rHMGB1 promotes NRF2 independent mitochondrial fusion via CXCR4\/PSMB5 pathway\u2010mediated Drp1 proteolysis. rHMGB1 may influence mitochondrial and endothelial function through this effect on mitochondrial dynamics.<\/jats:p>","DOI":"10.1155\/2021\/9993240","type":"journal-article","created":{"date-parts":[[2021,8,3]],"date-time":"2021-08-03T22:50:09Z","timestamp":1628031009000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Recombinant High\u2010Mobility Group Box 1 (rHMGB1) Promotes NRF2\u2010Independent Mitochondrial Fusion through CXCR4\/PSMB5\u2010Mediated Drp1 Degradation in Endothelial 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