{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:09:42Z","timestamp":1789711782513,"version":"4.0.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32170618"],"award-info":[{"award-number":["32170618"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["KLSB2023KF-02"],"award-info":[{"award-number":["KLSB2023KF-02"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017596","name":"Natural Science Basic Research Program of Shaanxi Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100017596","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Seronegative myasthenia gravis (SNMG) is a clinically heterogeneous subtype of myasthenia gravis (MG) that lacks the classical pathogenic autoantibodies used in routine diagnosis, leaving the underlying mechanisms poorly defined. Integrative genetic and single-cell transcriptomic analyses identified\n                    <jats:italic>VARS2<\/jats:italic>\n                    as an MG-associated candidate gene with particular relevance to SNMG.\n                    <jats:italic>VARS2<\/jats:italic>\n                    dysregulation was predominantly observed in CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, especially in the SNMG subgroup. To evaluate its\n                    <jats:italic>in vivo<\/jats:italic>\n                    relevance to SNMG, we established a zebrafish\n                    <jats:italic>vars2<\/jats:italic>\n                    knockdown model.\n                    <jats:italic>vars2<\/jats:italic>\n                    deficiency induced a myasthenia-like phenotype characterized by impaired locomotor activity, abnormal skeletal muscle development, defective motor neuron formation, and reduced expression of neuromuscular junction-related genes. Furthermore, the loss of\n                    <jats:italic>vars2<\/jats:italic>\n                    disrupted mitochondrial homeostasis, evidenced by mitochondrial structural damage, membrane potential loss, increased reactive oxygen species accumulation, and suppression of metabolic pathways. These changes were accompanied by immune dysregulation, marked by CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell\/Th17-associated inflammatory activation, reduced expression of Treg-related genes, and increased neutrophil and macrophage recruitment. Crucially, pharmacological interventions partially reversed these defects through mitochondrial support (CoQ10), acetylcholinesterase inhibition (Neostigmine), and targeted immune suppression (ML604440 for Th17 differentiation, GSK805 for Th17 function, and UNBS5162 for CXCL-related signaling). Together, these findings suggest that VARS2 links mitochondrial dysfunction to immune imbalance and neuromuscular injury in SNMG. Our study highlights mitochondrial immunometabolism as a candidate mechanistic axis and identifies VARS2 as a potential biomarker for SNMG-related immune remodeling.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1861435","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:38:52Z","timestamp":1789709932000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["VARS2 deficiency drives seronegative myasthenia gravis pathology via mitochondrial, immune, and neuromuscular dysregulation"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhaojie","family":"Lyu","sequence":"first","affiliation":[{"name":"Center for Automated and Innovative Drug Discovery, College of Life Sciences, Northwest University","place":["Xi\u2019an, Shaanxi, China"]},{"name":"Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Medicine, Northwest 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