From physiological homeostasis to pathological injury: Cell-specific functions, imbalance mechanisms, and disease biomarker value of brain lipid droplets

Int Immunopharmacol. 2026 Sep 10;189:117363. doi: 10.1016/j.intimp.2026.117363. Online ahead of print.

ABSTRACT

Lipid droplets (LDs) are versatile cellular structures that consist of a core made of neutral lipids, surrounded by a monolayer of phospholipid membrane. Beyond energy storage, LDs serve as critical immunometabolic platforms that govern microglial activation states and neuroinflammatory cascades. Their formation and function are regulated by specific proteins, making them key carriers for maintaining brain energy metabolism and lipid homeostasis. This article systematically reviews the research progress in the field of brain LDs: it clarifies the core biogenesis mechanisms, including endoplasmic reticulum (ER) membrane curvature and sequentially coordinated independent functions of ER-localized Berardinelli-Seip congenital lipodystrophy type 2 protein (Seipin) and fat storage-inducing transmembrane protein 2 (FIT2), as well as their dual physiological roles as energy reserves and lipid buffers; it systematically characterizes widespread LD distribution across nearly all physiological central nervous system(CNS) cell populations, with prominent cell-type heterogeneity in LD abundance, neutral lipid composition and metabolic turnover dynamics noting that the formation, metabolic state, and stress response of LDs are closely related to different cell types; it analyzes how the imbalance between LD synthesis and turnover drives microglia-mediated neuroinflammation and lipotoxicity across neurodegenerative diseases (NDDs), ischemic stroke, gliomas, and CNS infections. We specifically highlight the cell-type-specific and disease-stage-dependent pharmacological modulation of LD pathways-such as Adipose triglyceride lipase (ATGL)/diacylglycerol acyltransferase (DGAT)-directed lipolysis/lipogenesis and TREM2-mediated immunometabolic reprogramming-as a stratified strategy to suppress pathological neuroinflammation while preserving physiological lipid buffering, confirming that abnormal LDs are important triggers and markers of brain diseases. Abnormal LDs trigger microglia-mediated neuroinflammation, which serves as a key link in the progression of brain diseases such as Alzheimer’s disease (AD). Finally, it points out core unresolved issues such as the interaction between LDs and cellular signaling networks, and the functional heterogeneity of brain regions. This review integrates 2024-2026 in vivo imaging and multi-omic data, taking lineage-unified quantitative comparison of cell-type LD heterogeneity as the core analytical framework. On this basis, it systematically elaborates the closed-loop metabolic network of LD synthesis, lipolysis and lipophagy, summarizes the load-dependent biphasic regulatory mechanism of LDs across multiple CNS disorders, and further constructs an immunopharmacology-centered translational system: we clarify how dysregulated lipid metabolism drives microglial innate neuroinflammation, and sort out cell- and stage-selective ATGL/DGAT druggable targets together with cell-specific LD pathological biomarkers, which fills the fragmented discussion gap of existing neuro-lipid reviews.

PMID:42721506 | DOI:10.1016/j.intimp.2026.117363