Microglial pyroptosis in neurological disorders: mechanistic crosstalk, metabolic triggers, and therapeutic frontiers.

Neurodegenerative diseases (NDDs) are characterized by the progressive decline of neuronal structure and function, with neuroinflammation and neuronal death as key pathogenic features. Pyroptosis, a highly inflammatory kind of programmed cell death (PCD) facilitated by gasdermin (GSDM) proteins and inflammasome activation, has garnered significant attention among new mechanisms. The increased expression of pyroptosis-related proteins, frequently co-localized with misfolded protein aggregates, indicates a crucial involvement in the advancement of different NDDs. Further, microglial pyroptosis exacerbates neuronal damage by hindering the removal of neurotoxic chemicals and intensifying inflammatory responses. Epigenetic and post-translational modifications (PTMs) of histone and non-histone proteins, along with metabolic dysregulation, significantly influence pyroptotic signaling, ultimately expediting neurodegeneration. Pyroptosis, owing to its pivotal involvement in inflammation and neuronal demise, is gaining recognition as a possible diagnostic and prognostic biomarker, particularly in the advancement of immunotherapeutic approaches. Herein, we thoroughly examine the molecular control of pyroptosis through PTMs and metabolic pathways, its implications for neurodegenerative and neuropsychiatric disorders, and recent therapeutic developments aimed at targeting pyroptotic pathways. It emphasizes the advancement of novel diagnostic instruments, such as genetic reporters and nanomaterial-based molecular probes for the real-time and non-invasive identification of pyroptotic activity. These discoveries establish a foundation for future tailored treatment strategies designed to alleviate pyroptosis-induced neuroinflammation and neurodegeneration. HIGHLIGHTS: 1. Pyroptosis is a pro-inflammatory cell death linked to neuroinflammatory conditions. 2. ROS and oxidative stress connect pyroptosis with other cell death mechanisms. 3. Altered glucose and lipid metabolism influence pyroptosis and neuronal degeneration. 4. PTMs of GSDMD, caspase-1, and ASC regulate pyroptosis in brain disorders. 5. Targeting microglial pyroptosis offers potential therapy for neurodegenerative diseases.