ObjectivesTraumatic　brain　injury　(TBI)　is　a　primary　contributor　to　chronic　functional　impairment　in　human　populations,　initiating　complex　neuroinflammatory　cascades　and　neurodegeneration.　Despite　extensive　research　efforts,　the　precise　pathophysiological　pathways　remain　incompletely　characterized.　This　investigation　aims　to　establish　a　novel　therapeutic　strategy　that　targets　critical　molecular　pathways　post-injury,　potentially　addressing　the　current　limitations　in　the　clinical　management　of　TBI　patients.MethodsThe　single-cell　data　of　cortical　tissue　from　mice　with　TBI　were　obtained　from　public　databases　(GSE160763),　which　was　utilized　to　identify　alterations　in　in　the　composition　of　disease-associated　cells　and　related　molecules　as　the　disease　progresses.　Functional　and　pathway　enrichment　analyses　were　conducted　to　elucidate　the　functional　characteristics　of　microglia　and　astrocyte　subpopulations.　Trajectory　analysis　was　employed　to　investigate　cell　differentiation　characteristics.　Subsequently,　we　examined　the　expression　and　function　of　microglia-specific　molecules,　such　as　IFI204,　along　with　their　underlying　molecular　mechanisms　using　Western　blotting,　immunofluorescence,　co-immunoprecipitation　(CO-IP),　histopathology,　behavioral　tests,　and　molecular　docking　to　assess　binding　status,　as　well　as　molecular　dynamics　simulations.　Finally,　we　used　molecular　docking　technology　to　find　small　molecule　compounds　that　IFI204　can　stably　bind　to.ResultsWe　identified　nine　major　cell　populations,　most　of　which　undergo　dynamic　changes　following　TBI.　Astrocytes　and　microglia　were　the　predominant　populations　in　each　group,　and　further　cluster　analysis　revealed　that　the　proportions　of　interferon　(IFN)　and　axonogenesis-related　microglial　subtypes　increased　after　TBI.　Trajectory　inference　analysis　indicated　that　the　expression　of　Ifi204　is　upregulated　in　microglia　during　disease　progression.　Conditional　microglial　knockdown　of　IFI204　significantly　improved　neurological　deficits　in　mice,　and　alleviated　mitochondrial　dysfunction　and　microglial　pyroptosis.　Mechanistically,　SENP7,　identified　as　a　novel　molecule,　interacts　with　IFI204　in　microglia,　catalyzes　the　deSUMOylation　of　IFI204,　and　promotes　STING　signal　activation,　ultimately　driving　microglial　pyroptosis　and　mitochondrial　dysfunction.ConclusionsThe　interaction　between　IFI204　and　SENP7　promotes　microglial　pyroptosis　and　related　mitochondrial　dysfunction.　Furthermore,　in　the　case　of　TBI,　we　hypothesize　that　targeting　IFI204　might　yield　therapeutic　benefits.