Fenofibrate mitigates microglial activation by reprogramming lipid metabolism and inhibiting ferroptosis

Abstract Microglial activation is a central mediator of neuroinflammatory and neurodegenerative processes. Growing evidence indicates that dysregulated lipid metabolism and ferroptosis drive microglial dysfunction, yet pharmacological interventions targeting these interconnected pathways remain scarce. Fenofibrate is well-documented for its anti-inflammatory and antioxidant effects; nevertheless, its influence on microglial lipid metabolism and ferroptotic signaling remains unexplored. The present study was designed to examine the effects of fenofibrate on lipid remodeling, oxidative stress, and ferroptosis in human HMC3 microglia activated with lipopolysaccharide (LPS) and interferon-γ (IFN-γ). HMC3 cells were pre-treated with fenofibrate followed by inflammatory activation. Cell viability, cytokine secretion, oxidative stress, lipid droplet (LD) accumulation, and ferroptosis-associated markers were analyzed by ELISA, fluorescence imaging, qRT-PCR, and Western blotting. Fenofibrate decreased the production of TNF-α, IL-1β, and IL-6, restored mitochondrial membrane potential, and suppressed ROS and malondialdehyde (MDA) generation while increasing intracellular glutathione (GSH). The treatment markedly decreased LD accumulation by downregulating the lipid metabolism–related enzymes PLIN2, DGAT1, and GPAT4. Functional assays demonstrated enhanced fatty acid oxidation and restored lipolysis, directly confirming reprogrammed lipid catabolism. Moreover, fenofibrate attenuated ferroptotic stress, evidenced by reduced intracellular Fe²⁺ levels, decreased ACSL4 expression, and significant increase of the ferroptosis-protective enzyme GPX4. These molecular changes were accompanied by improved cell survival and decreased oxidative damage, suggesting that fenofibrate may partially modulate metabolic and and redox balance in activated microglia under in vitro conditions. In conclusion, these findings suggest that fenofibrate may exert protective effects by modulating lipid metabolism and suppressing ferroptosis-related pathways in activated microglia.