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Published on: August 15, 2012
IRG1/Itaconate Inhibits Microglial Senescence-Like Transition by Modulating Mitochondrial Dynamics through Rhoa
Zeyu Zhang1,2, Yanlin Chen1,2, Weizhen Gao1
1Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Aging and Disease
|June 29, 2026
Summary
Aging worsens brain injury after subarachnoid hemorrhage (SAH). This study reveals the immune-responsive gene 1 (IRG1)/itaconate pathway protects against SAH by regulating microglial senescence and mitochondrial function, offering a potential therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Metabolism
Background:
- Aging is a significant risk factor for poor outcomes following subarachnoid hemorrhage (SAH).
- The molecular mechanisms driving age-related exacerbation of early brain injury after SAH are not fully understood.
- Microglial senescence and neuroinflammation play critical roles in SAH pathogenesis.
Purpose of the Study:
- To investigate the role of the immune-responsive gene 1 (IRG1)/itaconate axis in the immunometabolic regulation of microglial senescence after SAH.
- To elucidate the molecular mechanisms by which IRG1 and itaconate exert neuroprotective effects in the context of SAH.
- To explore the therapeutic potential of targeting the IRG1/itaconate pathway for mitigating age-related brain injury.
Main Methods:
- Utilized aged and young mouse models subjected to SAH.
- Investigated microglia-specific IRG1 deficiency and its impact on brain injury, senescence, and mitochondrial dynamics.
- Employed click chemistry-based proteomics, site-directed mutagenesis, and treatment with itaconate derivatives (4-octyl itaconate) to identify molecular targets and assess therapeutic efficacy.
Main Results:
- Endogenous IRG1 and itaconate upregulation is a protective response to SAH, which is diminished in aged mice.
- Microglia-specific IRG1 deficiency accelerated SAH-induced brain injury, promoting microglial senescence and SASP factor secretion.
- Itaconate directly alkylates RhoA at Cys107, inhibiting ROCK1 activation and suppressing Drp1-mediated mitochondrial fragmentation; 4-octyl itaconate treatment rescued deficits.
Conclusions:
- The IRG1/itaconate-RhoA-Drp1 axis represents a novel metabolic-mitochondrial checkpoint crucial for regulating microglial senescence and brain injury after SAH.
- Impaired IRG1/itaconate signaling contributes to age-related exacerbation of neuroinflammation and poor outcomes in SAH.
- Restoring this pathway via itaconate derivatives is a promising therapeutic strategy for improving SAH patient outcomes.