# Metabolic control of neuroinflammation: focus on itaconate and its derivatives in CNS disorders

## TL;DR

Itaconate and its derivatives help control brain inflammation by changing microglial metabolism, offering potential treatments for diseases like Alzheimer’s and stroke.

## Contribution

This paper reviews how itaconate and its derivatives regulate microglial metabolism and inflammation, suggesting new metabolic interventions for CNS disorders.

## Key findings

- Itaconate inhibits NF-κB and NLRP3 while activating Nrf2 and suppressing SDH in microglia.
- Structurally optimized itaconate derivatives show improved pharmacokinetics and bioactivity for treating CNS disorders.
- Itaconate-based interventions offer neuroprotection in diseases like Alzheimer’s and ischemic stroke.

## Abstract

The activation of microglia, which are the resident immune cells of the central nervous system (CNS), underpins the pathogenesis of neuroinflammatory and neurodegenerative diseases. Metabolic reprogramming has recently been recognized as a critical mechanism that regulates microglial activation because distinct activation phenotypes are tightly coupled to specific metabolic profiles that shape their functional and inflammatory responses. Accumulating evidence indicates that microglia produce itaconate through the tricarboxylic acid cycle, and itaconate and its derivatives play key antioxidant and anti-inflammatory roles. Mechanistically, itaconate has a major impact on the metabolic processes and functional state of microglia by blocking the NF-κB signaling route, activating the Nrf2 signaling pathway, and inhibiting succinate dehydrogenase synthesis as well as NLRP3 inflammatory vesicle activation. Collectively, these actions confer significant protection against CNS disorders, including ischemic stroke, Alzheimer’s disease, Parkinson’s disease, and cerebral hemorrhage. Furthermore, structurally optimized itaconate derivatives exhibit enhanced pharmacokinetics and bioactivity. This review highlights the pivotal role of itaconate and its derivatives in microglial regulation, explores their therapeutic potential in neurological diseases, and outlines future research directions, with the aim of providing a theoretical foundation for novel metabolic interventions.

Metabolic control of neuroinflammation by itaconate. Itaconate reprograms microglial metabolism to exert neuroprotection. This multifaceted action involves inhibiting NF-κB and NLRP3, activating Nrf2, and suppressing succinate dehydrogenase (SDH). Structurally optimized itaconate derivatives thus emerge as promising metabolic interventions for cerebral hemorrhage, Alzheimer’s disease, and ischemic stroke, highlighting the therapeutic potential of targeting the immunometabolic crosstalk.Illustration depicting the role of itaconate in neuroinflammation within CNS disorders. On the left, glucose converts through the TCA cycle to affect microglia. Inactive microglia transition to active with inflammatory signals. Itaconate is shown blocking NF-κB, activating Nrf2, inhibiting SDH, and suppressing NLRP3, leading to neuroprotection and metabolic reprogramming. Future directions suggest structure-optimized interventions to enhance efficacy, aiming at conditions like cerebral hemorrhage, Alzheimer’s disease, and ischemic stroke.

Metabolic control of neuroinflammation by itaconate. Itaconate reprograms microglial metabolism to exert neuroprotection. This multifaceted action involves inhibiting NF-κB and NLRP3, activating Nrf2, and suppressing succinate dehydrogenase (SDH). Structurally optimized itaconate derivatives thus emerge as promising metabolic interventions for cerebral hemorrhage, Alzheimer’s disease, and ischemic stroke, highlighting the therapeutic potential of targeting the immunometabolic crosstalk.