Inhibition of the calcineurin/forkhead box O1/fatty acid binding protein 4 pathway prevents SERCA2 dysfunction‐induced foam cell formation and atherosclerosis

Background and Purpose The cysteine residue 674 (C674) of sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 2 (SERCA2) is pivotal in maintaining SERCA2 activity. The C674S mutation leads to SERCA2 dysfunction and exacerbates atherosclerosis by inducing endoplasmic reticulum stress and inflammation in bone marrow‐derived macrophages (BMDMs) and endothelial cells (ECs). This study aimed to explore if SERCA2 dysfunction aggravates atherosclerosis, by disrupting fatty acid metabolism and promoting the formation of macrophage foam cells. Experimental Approach Heterozygous SERCA2 C674S gene mutation knock‐in (SKI) mice were used to simulate SERCA2 dysfunction under pathological conditions. Serum from SKI mice and their littermate wild‐type mice were taken for metabolomic testing. The entire aorta and aortic root were isolated for histological analysis. BMDMs were used for protein expression, lipid uptake and accumulation analysis. Key Results In SKI BMDMs, SERCA2 dysfunction induced the expression of calcineurin (CaN), which promoted nuclear translocation of forkhead box O1 (FoxO1) and transcription of its downstream target fatty acid‐binding protein 4 (FABP4), leading to increased fatty acid synthesis and foam cell formation. Inhibition of the CaN/FoxO1/FABP4 pathway corrects aberrant lipid metabolism and inhibits the formation of foam cells in SKI BMDMs. Pharmacological interventions targeting either FoxO1 or FABP4, or FABP4 partial deficiency, significantly ameliorated atherosclerosis progression. Conclusions and Implications SERCA2 dysfunction accelerates the progression of atherosclerotic lesions by stimulating the CaN/FoxO1/FABP4 pathway and promoting the formation of foam cells. Our findings highlight the importance of SERCA2 function in the context of atherosclerosis and reveal a novel therapeutic strategy to combat lipid accumulation and atherosclerosis.