Multi-omics identifies PCK1-associated immunometabolic regulation underlying the protective effects of sinomenine in vascular dementia

Background Vascular dementia (VaD) is one of the major causes of cognitive impairment among older adults. However, effective treatments that can modify the progression of the disease are still lacking. Emerging evidence indicates that metabolic remodeling in microglia influences inflammatory responses during vascular brain injury. Microglial immunometabolic regulation has therefore been proposed as an important contributor to the pathogenesis of vascular dementia (VaD). Methods Transcriptomic integration, WGCNA, network pharmacology, and single-nucleus RNA sequencing were combined to identify disease-associated microglial alterations and potential targets involved in sinomenine (SIN)-mediated regulation. The interaction between SIN and phosphoenolpyruvate carboxykinase 1 (PCK1) was investigated using molecular docking and molecular dynamics simulations. The biological effects of SIN were then validated in lipopolysaccharide (LPS)-stimulated BV2 microglia. Results Integrated analyses highlighted PCK1 as a potential mediator associated with SIN-induced metabolic regulation in VaD. snRNA-seq demonstrated expansion of metabolically stressed microglial states accompanied by PCK1-related metabolic alterations. Stable binding between SIN and PCK1 was supported by molecular docking and molecular dynamics simulations. In LPS-stimulated BV2 microglia, SIN suppressed inflammatory activation, restored PCK1 expression, attenuated inflammation-associated metabolic remodeling, improved cellular bioenergetics, and modulated metabolic redox-related parameters. SIN also enhanced adaptive stress responses through regulation of CRYAB, APOD, and HSPH1. Conclusion Collectively, these findings suggest that SIN alleviates VaD-associated microglial dysfunction by modulating PCK1-associated immunometabolic alterations. They expand the current understanding of the pharmacological actions of SIN and highlight microglial immunometabolic regulation as a potential therapeutic target for VaD.