Remodeling of macrophage lipid metabolism by phytosterol suppresses inflammation: Insights from targeted lipidomics

Phytosterols are widely recognized bioactive compounds exhibiting anti-inflammatory effects. Macrophages adopt a distinct lipid metabolic state during inflammatory responses. However, the specific mechanisms by which phytosterols influence macrophage lipid metabolism and subsequently regulate inflammation through metabolic remodeling remain unclear. In this study, we elucidate how phytosterols reprogram macrophage lipid metabolism to attenuate inflammatory responses. Quantitative lipidomic analysis revealed that phytosterol-induced lipid remodeling predominantly affects long-chain triglycerides. Further mechanistic studies demonstrated that phytosterols increase lipid droplet accumulation and regulate their metabolism by suppressing adipose triglyceride lipase (ATGL), upregulating hypoxia inducible lipid droplet associated proteins (HILPDA), and reducing the production of pro-inflammatory intermediates, including arachidonic acid. Consequently, phytosterol treatment decreased prostaglandin E₂ (PGE₂) levels and reduced the secretion of pro-inflammatory cytokines such as IL-1β. Collectively, these findings provide novel mechanistic insights into how phytosterols reduce macrophage-driven inflammation through lipid metabolic reprogramming.