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Beyond its known function in necroptosis, MLKL was found to control HSV\u20101 transport into the nucleus, tightly regulated by Optineurin (OPTN). We evidenced an essential regulatory interaction between MLKL and OPTN, governing MLKL's activity in both necroptosis\u2010dependent and independent pathways. In vivo, studies using Optn knockout mice demonstrated how this MLKL\u2010OPTN axis contributes to demyelination and neurological symptoms mimicking MS. This axis critically prevents oligodendrocyte death and the associated demyelination during HSV\u20101 infection. Furthermore, pharmacological interventions with Necrosulfonamide (NSA), an MLKL inhibitor, showed therapeutic potential in preserving myelin integrity and reducing neurological deficits in HSV\u20101\u2010infected models, suggesting a viable strategy for managing virus\u2010induced neurodegeneration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings highlight the significant role of MLKL in HSV\u20101 pathogenesis and suggest that MLKL dysregulation is a key mechanism behind severe neurological damage.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>MLKL plays a significant role in regulating endosomal transport of HSV\u20101 to nucleus during early stages of infection.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Formation of p\u2010MLKL bodies during HSV\u20101 infection leads to death of oligodendrocyte and subsequent demyelination.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>OPTN can negatively modulate MLKL levels to restrict infection and consequential oligodendrocyte death during HSV\u20101 infection.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70353","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T04:36:57Z","timestamp":1749530217000},"source":"Crossref","is-referenced-by-count":1,"title":["MLKL\u2012OPTN axis regulates herpesvirus\u2010induced neurological sequelae"],"prefix":"10.1002","volume":"15","author":[{"given":"Ilina","family":"Bhattacharya","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences University of Illinois Chicago  Chicago Illinois USA"},{"name":"Department of Microbiology and Immunology University of Illinois Chicago  Chicago Illinois 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