IDH1 Promotes Foam Cell Formation by Aggravating Macrophage Ferroptosis

Area of Science:

• Biochemistry
• Cell Biology
• Molecular Medicine

Background:

• Ferroptosis is characterized by iron accumulation and impaired antioxidant capacity, leading to cell death via lipid peroxides.
• Foam cell formation is implicated in atherosclerosis, a condition driven by lipid accumulation in macrophages.

Purpose of the Study:

• To investigate if inhibiting isocitrate dehydrogenase 1 (IDH1) can prevent oxidized low-density lipoprotein (ox-LDL)-induced ferroptosis and foam cell formation in macrophages.
• To explore the role of IDH1 in activating nuclear factor erythroid 2-related factor 2 (NRF2) signaling.

Main Methods:

• Gene expression profiling (GSE70126, GSE70619) and bioinformatics analysis to identify key genes.
• Experimental confirmation of ox-LDL effects on macrophage ferroptosis and IDH1 levels.
• Treatment with ferroptosis inhibitor (Fer-1) and IDH1 inhibition to assess molecular changes.

Main Results:

• Ox-LDL significantly increased macrophage ferroptosis and IDH1 levels.
• IDH1 inhibition reduced ferroptosis markers (Fe2+, lipid peroxidation, LDH, GSH depletion) and increased protective proteins (GPX4, FTH1, SLC7A11).
• IDH1 inhibition suppressed ox-LDL-induced macrophage damage and apoptosis, while increasing NRF2 levels.

Conclusions:

• Inhibiting IDH1 effectively reduces ox-LDL-induced ferroptosis and foam cell formation in macrophages.
• IDH1 plays a critical role in regulating foam cell formation.
• IDH1 inhibition presents a promising therapeutic strategy for atherosclerosis.