The impact of lactate and lipid metabolism in microglia upon cognitive impairment following radiation-induced brain injury.

BACKGROUND: Radiation-induced brain injury (RIBI) is a serious complication that occurs after cranial radiotherapy. The main manifestations are delayed radiation effects characterized by neuroinflammation and damage to neural stem cell populations. Microglia, the resident immune cells of the central nervous system (CNS), have become key mediators in the pathological process of RIBI. This review aims to systematically elucidate how metabolic reprogramming of lactate and lipid pathways in microglia contributes to chronic neuroinflammation and cognitive impairment following RIBI, and to evaluate the therapeutic potential of targeting these metabolic pathways.

MAIN BODY: Ionizing radiation (IR) triggers intense activation of microglia, which initiates and maintains a chronic neuroinflammatory state characterized by the release of cytotoxic mediators and changes in phagocytic function. Changes in lactate and lipid metabolism within microglia are crucial in their response to neuroinflammation and neurodegeneration. Activated microglia typically change their metabolism from oxidative phosphorylation (OXPHOS), which uses oxygen to generate energy, to a process called aerobic glycolysis, which leads to increased lactate production. This metabolic shift, combined with the role of lactate as a signaling molecule and a substrate for epigenetic modifications (lactylation), can significantly influence the inflammatory outcome. Additionally, dysregulation of lipid metabolism, such as accumulation of lipid droplets (LDs), represents a pro-inflammatory, dysfunctional state known as lipid droplet accumulation-type microglia (LDAM), and is associated with impaired phagocytosis and persistent inflammation. This article summarizes the pathological mechanisms of RIBI, with a focus on the complex roles of lactate and lipid metabolism in microglia. It explores how radiation induces microglial activation and metabolic transformation. The article also discusses the dual role of lactate, the effects of lipid dysregulation, and potential interactions between metabolic pathways. Finally, it highlights how these factors commonly relate to impaired inflammatory responses and disruptions in neural repair processes, such as neurogenesis and oligodendrocyte generation.

CONCLUSIONS: By studying how changes in microglial metabolism lead to neuronal dysfunction and cognitive decline in RIBI, this review provides a new perspective for regulating microglial metabolic pathways to alleviate radiation-induced cognitive impairment.