Microglia play a pivotal role in neuroinflammation, which is a significant contributor to various neurodegenerative diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Recent studies have highlighted the ZBP1-RIPK1 signaling pathway in microglia as a crucial driver of inflammation in AD, where ZBP1 is activated by mitochondrial Z-DNA, suggesting potential therapeutic targets (ref: Gertie doi.org/10.1016/j.immuni.2025.09.010/). In ALS, the C9orf72 hexanucleotide repeat expansions were shown to impair microglial responses, indicating that genetic factors can significantly influence microglial function and neuroinflammatory responses (ref: Masrori doi.org/10.1038/s41593-025-02075-1/). Furthermore, the loss of MFE-2, an enzyme involved in lipid metabolism, was found to exacerbate neuroinflammation and AD pathology, linking metabolic dysregulation to inflammatory processes in microglia (ref: Gao doi.org/10.1038/s43587-025-00976-1/). These findings collectively underscore the importance of microglial metabolism and signaling pathways in modulating neuroinflammatory responses in neurodegenerative diseases. In addition to genetic and metabolic factors, the microglial response to injury is also critical. For instance, the development of an immuno-piezoelectric transducer has been shown to reprogram the neuroimmune microenvironment following traumatic brain injury (TBI), promoting an anti-inflammatory microglial phenotype and enhancing neural stem cell therapy (ref: Liang doi.org/10.1002/adma.202512810/). The interaction between regulatory T cells and microglia in spinal cord injury further illustrates the complex dynamics of immune responses in the central nervous system, where Treg cells help regulate microglial cholesterol metabolism and preserve their function (ref: Qin doi.org/10.1016/j.neuron.2025.09.001/). Overall, these studies highlight the multifaceted roles of microglia in neuroinflammation and their potential as therapeutic targets in neurodegenerative diseases.

Microglia are increasingly recognized for their critical roles in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). In AD, the activation of microglial ZBP1-RIPK1 signaling has been implicated in driving neuroinflammation, suggesting that targeting this pathway could offer new therapeutic avenues (ref: Gertie doi.org/10.1016/j.immuni.2025.09.010/). Additionally, the impairment of microglial responses due to C9orf72 hexanucleotide repeat expansions in ALS indicates that genetic mutations can significantly affect microglial function and contribute to disease progression (ref: Masrori doi.org/10.1038/s41593-025-02075-1/). Furthermore, the loss of MFE-2 in microglia has been linked to dysregulated lipid metabolism and increased neuroinflammation in AD, highlighting the interplay between metabolic processes and immune responses in neurodegenerative conditions (ref: Gao doi.org/10.1038/s43587-025-00976-1/). Moreover, the modulation of O-GlcNAc cycling has been shown to influence α-synuclein pathology in PD, suggesting that metabolic alterations in microglia can affect the aggregation and degradation of neurotoxic proteins (ref: Miao doi.org/10.1186/s13024-025-00904-2/). The study of microglial deletion of Hrh4 has demonstrated that enhancing microglial phagocytosis can alleviate AD pathology by promoting the clearance of amyloid-beta and tau aggregates (ref: Xu doi.org/10.1002/advs.202505421/). These findings illustrate the complex relationship between microglial function, neuroinflammation, and neurodegenerative disease pathology, emphasizing the need for further research into microglial-targeted therapies.

Microglial metabolism and lipid homeostasis are crucial for maintaining brain health and function, particularly in the context of neurodegenerative diseases. Recent research has identified that the transcription factor MEF2C is essential for microglial function, with its loss leading to a hyperinflammatory phenotype characterized by lipid accumulation and lysosomal dysfunction (ref: Nguyen doi.org/10.1038/s41590-025-02299-0/). This suggests that transcriptional and epigenetic regulation of microglial metabolism is vital for preventing neuroinflammation. Additionally, studies have shown that microglia selectively regulate lipid accumulation in Alzheimer's disease models, indicating that lipid metabolism is intricately linked to disease pathology (ref: Xu doi.org/10.1038/s41467-025-64161-z/). Moreover, the accumulation of lipid droplets in microglia has been associated with high-fat diet-induced cognitive impairment, where the molecule feimin has been proposed as a negative regulator of lipid accumulation and inflammation (ref: Gao doi.org/10.1002/advs.202512023/). This highlights the potential for targeting lipid metabolism in microglia as a therapeutic strategy for cognitive decline. Furthermore, the study of microglial Rack1 deficiency has revealed its role in enhancing astrocytic phagocytosis and reducing neuroinflammation, further emphasizing the importance of lipid homeostasis in microglial function and its implications for neurodegenerative diseases (ref: Zhang doi.org/10.1002/advs.202515877/). Collectively, these findings underscore the critical role of microglial metabolism in maintaining brain health and its potential as a therapeutic target in neurodegenerative conditions.

The response of microglia to injury and disease is a complex and dynamic process that plays a crucial role in the outcome of various neurological conditions. Following traumatic brain injury (TBI), microglia can adopt different phenotypes, with recent studies demonstrating that immuno-piezoelectric transducers can reprogram the neuroimmune microenvironment to promote an anti-inflammatory response, thereby enhancing neural stem cell therapy (ref: Liang doi.org/10.1002/adma.202512810/). This innovative approach highlights the potential for engineering microglial responses to improve recovery after injury. Additionally, the partnership between regulatory T cells and microglia has been shown to preserve Treg cell function and regulate cholesterol metabolism in the injured spinal cord, indicating that immune cell interactions are critical for recovery (ref: Qin doi.org/10.1016/j.neuron.2025.09.001/). Moreover, the fate mapping of macrophages after TBI has revealed a long-lasting population with distinct transcriptomic signatures, suggesting that peripheral immune cells also contribute to the neuroinflammatory response and long-term outcomes following injury (ref: Paladini doi.org/10.1038/s41467-025-63952-8/). In the context of neurodegenerative diseases, modulation of O-GlcNAc cycling has been implicated in the amplification and degradation of α-synuclein, linking metabolic processes to neuroinflammatory pathology (ref: Miao doi.org/10.1186/s13024-025-00904-2/). These findings collectively emphasize the importance of understanding microglial responses to injury and disease, as they hold the key to developing effective therapeutic strategies for neuroprotection and recovery.

Microglia have emerged as critical players in the pathophysiology of psychiatric disorders, with recent studies highlighting their role in anxiety and stress-related conditions. For instance, the activation of microglia in the hippocampus has been linked to airway hyperresponsiveness and anxiety comorbidity, showcasing how neuroinflammation can influence emotional and behavioral outcomes (ref: Zhang doi.org/10.1186/s12974-025-03565-6/). This activation is characterized by morphological changes and increased expression of inflammatory markers, suggesting that targeting microglial activation may offer therapeutic potential for anxiety disorders. Additionally, systemic inflammation has been shown to induce anxiety through microglial engulfing of nucleus accumbens inputs, leading to diminished excitability of D1 receptor neurons, which are crucial for motivation and emotional regulation (ref: Nakajima doi.org/10.1016/j.bbi.2025.106154/). Furthermore, microglia-mediated loss of perineuronal nets has been implicated in social memory deficits following repeated neonatal sevoflurane exposure, indicating that early-life stressors can have lasting effects on microglial function and social behavior (ref: Shi doi.org/10.1016/j.bbi.2025.106148/). These findings underscore the importance of microglial function in psychiatric disorders and suggest that interventions targeting microglial activity may help alleviate symptoms associated with these conditions.

The genetic and molecular mechanisms underlying microglial function are critical for understanding their roles in health and disease. Recent research has developed high-resolution atlases of the early postnatal mouse brain, mapping GABAergic cells and microglia to elucidate their developmental trajectories (ref: Liwang doi.org/10.1038/s41467-025-64549-x/). This foundational work provides insights into how microglial populations evolve during brain development and their potential implications for neurodevelopmental disorders. Moreover, variants in the phospholipase C gamma 2 (PLCG2) gene, which is linked to Alzheimer's disease risk, have been shown to alter microglial state and function in induced pluripotent stem cell-derived microglia-like cells. These findings highlight the impact of genetic variations on microglial behavior and their contributions to neurodegenerative disease pathology (ref: Bedford doi.org/10.1002/alz.70772/). Additionally, the activation of the STING pathway has been implicated in microglial responses to herpes simplex virus infection, further illustrating the complex interplay between genetic factors and immune signaling in microglia (ref: Liu doi.org/10.1186/s12974-025-03595-0/). Collectively, these studies emphasize the importance of genetic and molecular mechanisms in shaping microglial function and their implications for various neurological disorders.

Therapeutic strategies targeting microglia are gaining traction in the quest to mitigate neurodegenerative diseases and psychiatric disorders. Recent studies have explored the role of LRRK2, a kinase primarily expressed in microglia, in modulating immune responses in Alzheimer's disease. LRRK2 deficiency has been shown to alleviate amyloid-beta deposition and associated pathology by reprogramming microglial activity, suggesting that targeting this pathway could provide a novel therapeutic approach (ref: Zhang doi.org/10.1038/s41398-025-03598-8/). Furthermore, the conditional knockout of Rack1 in microglia has demonstrated potential in reducing neuroinflammation and cognitive impairments in AD models, highlighting the therapeutic promise of modulating microglial function (ref: Zhang doi.org/10.1002/advs.202515877/). In addition to genetic modulation, immunotherapeutic approaches such as low-dose IL-2 treatment have shown promise in addressing immune dysregulation in Autism Spectrum Disorder (ASD), targeting T-cell imbalances and neuroinflammation to alleviate core symptoms (ref: Li doi.org/10.1038/s41398-025-03609-8/). Moreover, dual inhibition of phosphodiesterases 4 and 10 has been found to restore CREB1 function and enhance neuronal resilience in Alzheimer's disease models, indicating that targeting microglial signaling pathways can have broader implications for neuroprotection (ref: Rong doi.org/10.1186/s13195-025-01869-6/). These findings collectively underscore the potential of therapeutic strategies aimed at modulating microglial activity to improve outcomes in neurodegenerative and psychiatric disorders.

Microglial interactions with other cell types are crucial for maintaining homeostasis in the central nervous system and play significant roles in various neurological conditions. Recent studies have highlighted the importance of microglial interactions with astrocytes, particularly in the context of Alzheimer's disease. The conditional knockout of Rack1 in microglia has been shown to enhance astrocytic phagocytosis of amyloid-beta, thereby alleviating neuroinflammation and cognitive deficits in AD models (ref: Zhang doi.org/10.1002/advs.202515877/). This underscores the potential for targeting microglial-astrocytic interactions as a therapeutic strategy in neurodegenerative diseases. Additionally, the aberrant C1q-C3 complement signaling in microglia and astrocytes has been implicated in synaptic dysfunction and neuronal loss, particularly during epileptogenesis. Neutralization of C1q has been shown to attenuate complement-mediated synaptic elimination, suggesting that modulating these interactions could provide therapeutic benefits in epilepsy (ref: Jeong doi.org/10.1111/epi.18678/). Furthermore, the integration of genetic regulation and splicing quantitative expression in schizophrenia has identified novel risk genes that may influence microglial interactions, highlighting the complex interplay between genetic factors and microglial function in psychiatric disorders (ref: Li doi.org/10.1038/s41398-025-03633-8/). Collectively, these findings emphasize the critical role of microglial interactions with other cell types in shaping immune responses and their implications for therapeutic interventions.