• Protocatechualdehyde significantly reduces serum lipid levels and stabilizes atherosclerotic plaques in ApoE-/- mice.
• Transcriptomic analysis identified 191 differentially expressed genes, with Kprp, Calm4, Hrnr, and Lor as key candidate targets.
• RT-PCR validation confirmed that protocatechualdehyde downregulates Kprp, Calm4, and Lor mRNA expression, which were elevated in atherosclerotic mice.
• Kprp, Calm4, and Lor are potential therapeutic targets for protocatechualdehyde in treating atherosclerosis.