Assistant Professor University of Texas at San Antonio san Antonio, Texas, United States
Objectives: This study aimed to explore how exogenous monounsaturated fatty acids (MUFAs) influence ferroptosis sensitivity in human THP-1 differentiated macrophages, testing the hypothesis that MUFAs enhance ferroptosis resistance through modulation of lipid remodeling.
Methods: THP-1 monocytes were differentiated into macrophages using phorbol 12-myristate 13-acetate (PMA). Differentiated macrophages were treated with exogenous polyunsaturated fatty acid (PUFA, linoleic acid) and monounsaturated fatty acid (MUFA, oleic acid) and exposed to ferroptosis-inducing agents, including erastin, RSL3, and ML-210. Pro-inflammatory macrophages were induced via lipopolysaccharide (LPS) treatment. Cell death was assessed using real-time fluorescence probes, lactate dehydrogenase (LDH) release assays, and morphological analysis. Lipid remodeling effects were evaluated using BODIPY™ 493/503 staining, while MUFA-mediated inflammatory responses were analyzed through ELISA and real-time PCR for cytokines IL-6 and MCP-1.
Results: Exogenous oleic acid, but not linoleic acid, significantly inhibited ferroptosis in THP-1 differentiated macrophages, as indicated by reduced LDH release and diminished morphological changes. Similarly, LPS-treated macrophages exhibited increased resistance to ferroptosis and enhanced lipid droplet formation. Furthermore, oleic acid pre-treatment amplified the pro-inflammatory response to LPS stimulation, as shown by elevated cytokine gene expression levels of IL-6 and MCP-1. These results highlight the dual role of MUFAs in promoting ferroptosis resistance and enhancing inflammatory pathways.
Conclusions: Exogenous MUFAs confer resistance to ferroptosis and enhance the inflammatory response in human THP-1 differentiated macrophages by modulating lipid remodeling. These findings suggest that dietary MUFAs may contribute to chronic inflammatory conditions associated with macrophage accumulation in the vascular wall, such as atherosclerosis.
Funding Sources: This study was supported by the Trauma Research and Combat Casualty Care Collaborative (TRC4) and The University of Texas at San Antonio research grant.
