OBJECTIVE To explore the potential targets and signaling pathways of apilimod in regulating atherosclerosis(AS).

METHODS Target genes of apilimod were predicted using the SuperPred database, and core targets were screened through KEGG enrichment analysis and AS-related gene sets. MOE molecular docking and surface plasmon resonance(SPR) were employed to determined interactions between apilimod and PI3K/AKT pathway key proteins. The effects of apilimod on lipid metabolism, inflammatory cytokines, and cell cycle were assessed using oxidized low-density lipoprotein(ox-LDL)-induced vascular smooth muscle cells(VSMC) proliferation, acute hyperlipidemic mouse models, and ApoE-deficient mice.

RESULTS Apilimod targets were significantly enriched in the PI3K/AKT pathway. Molecular docking revealed high-affinity binding(binding energy<−5 kcal·mol⁻¹, RMSD<2Å) between apilimod and key targets, including PIK3CA, AKT1, and CDK4, ITGAV. The SPR results verified that there were highly affinity interactions between apilimod and PI3K, AKT1, and ITGAV proteins. Apilimod markedly inhibited ox-LDL-induced VSMC proliferation and blocked the G1/S phase transition. In ApoE-deficient mice, apilimod significantly reduced the level of IL-6 and TNF-α in serum, as well as the level of ICAM1 and VCAM1 in aortic, decreased lipid deposition with a 31%–35% decrease in aortic. Additionally, apilimod suppressed the transcription and protein expression of CDK4, CCND1, and EGFR and inhibited the PI3K/AKT-NF-κB/STAT3 signaling axis.

CONCLUSION Apilimod alleviates AS progression by targeting the PI3K/AKT pathway and integrin signaling, thereby inhibiting inflammation and VSMC proliferation. However, its efficacy is independent of lipid-lowering effects.