Effects of β‑hydroxybutyrate on restoring autophagic flux and mitochondrial function in macrophages exposed to oxidized low‑density lipoprotein

Atherosclerosis represents a major risk factor contributing to the development and advancement of cardiovascular diseases. The present study aimed to investigate the role of impaired autophagy and mitochondrial dysfunction in THP‑1 macrophages induced by oxidized low‑density lipoprotein (ox‑LDL), a key factor in atherosclerosis and cardiovascular disease. The molecular mechanism underlying the contribution of ox‑LDL to macrophage dysfunction is poorly understood. The present study aimed to determine whether β‑hydroxybutyrate (BHB) protects autophagic and mitochondrial function in THP‑1 macrophages exposed to ox‑LDL. Using cell culture, western blotting, autophagy detection assay and measurement of mitochondrial membrane potential, the present study evaluated the effect of BHB on autophagic flux and mitochondrial integrity. Ox‑LDL treatment markedly increased p62 protein levels and decreased LC3‑II/LC3‑I ratios, indicating impaired autophagy. BHB decreased p62 levels, increased LC3‑II/LC3‑I ratios and restored autophagic flux (shown by increased autophagosome numbers) and improved mitochondrial membrane potential. In addition, BHB downregulated STAT4, which was upregulated by ox‑LDL, suggesting a signaling pathway through which BHB exerts its protective effect. The present findings demonstrate that BHB enhances autophagic activity and mitochondrial function in THP‑1 macrophages under ox‑LDL stress, highlighting its potential as a novel therapeutic agent for metabolic and cardiovascular disease. Future studies should examine in vivo applications and the broader implications of BHB in atherosclerosis.