{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T01:54:50Z","timestamp":1788573290780,"version":"build-2803163510"},"reference-count":0,"publisher":"Aging and Disease","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Aging Dis"],"abstract":"<jats:p>Aging is a potent risk factor for poor prognosis in subarachnoid hemorrhage (SAH), yet the molecular mechanisms underlying the age-related exacerbation of early brain injury remain incompletely understood. This study investigates the immunometabolic regulation of the microglial senescence-like transition following SAH, focusing on the immune-responsive gene 1 (IRG1)\/itaconate axis. We observed that the endogenous upregulation of IRG1 and itaconate is a protective response to hemorrhagic stress that is significantly blunted in aged mice. Microglia-specific IRG1 deficiency exacerbated SAH-induced brain injury, characterized by an accelerated senescence-like transition and the secretion of senescence-associated secretory phenotype (SASP) factors. Mechanistically, we demonstrate that IRG1 deficiency leads to excessive mitochondrial fission and dysfunction via the hyperactivity of Dynamin-related protein 1 (Drp1). Using click chemistry-based proteomics and site-directed mutagenesis, we identified that itaconate exerts its neuroprotective effects by directly alkylating the small GTPase RhoA at the cysteine 107 (C107) residue. This specific post-translational modification inhibits RhoA-GTP binding and downstream ROCK1 activation, thereby suppressing Drp1-mediated mitochondrial fragmentation. Importantly, treatment with the cell-permeable itaconate derivative 4-octyl itaconate (4-OI) rescued mitochondrial dynamics and attenuated microglial senescence and neurological deficits, whereas the RhoA-C107S mutation abolished these protective effects. Collectively, our findings unveil a novel metabolic-mitochondrial checkpoint involving the IRG1\/itaconate-RhoA-Drp1 axis. Restoring this pathway represents a promising therapeutic strategy to combat the age-related exacerbation of neuroinflammation and improve outcomes in SAH patients.<\/jats:p>","DOI":"10.14336\/ad.2025.1527","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T17:01:06Z","timestamp":1782234066000},"source":"Crossref","is-referenced-by-count":1,"title":["IRG1\/Itaconate Inhibits Microglial Senescence-Like Transition by Modulating Mitochondrial Dynamics through Rhoa Alkylation in Subarachnoid Hemorrhage"],"prefix":"10.14336","member":"5462","published-online":{"date-parts":[[2026]]},"container-title":["Aging and Disease"],"original-title":[],"deposited":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T17:01:07Z","timestamp":1782234067000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.aginganddisease.org\/EN\/10.14336\/AD.2025.1527"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":0,"URL":"https:\/\/doi.org\/10.14336\/ad.2025.1527","relation":{},"ISSN":["2152-5250"],"issn-type":[{"value":"2152-5250","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026]]}}}