Objective <p>The present study aimed to clarify the function of miR-7641 in atherosclerosis (AS) and to elucidate the molecular basis of its modulation of ox-LDL-triggered autophagy in macrophages through Ubiquitin-Specific Protease 7 (USP7).</p> Methods <p>An in vitro AS model was generated by exposing human THP-1 macrophages to ox-LDL. Experimental manipulation included transfection with miR-7641 mimics, introduction of a USP7 overexpression plasmid, and administration of the autophagy inhibitor 3-methyladenine (3-MA). Transcript and protein levels were determined by RT-qPCR and Western blot, respectively. Cytokine release was assessed via ELISA. The binding interaction between miR-7641 and USP7 was validated using a dual-luciferase reporter assay.</p> Results <p>miR-7641 levels were markedly elevated in macrophages following ox-LDL stimulation. Forced expression of miR-7641 attenuated the synthesis and secretion of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. At the mechanistic level, miR-7641 counteracted ox-LDL-mediated inhibition of macrophage autophagy, as indicated by an increased LC3B-II/I ratio, enhanced Beclin-1 expression, and decreased P62 accumulation. Dual-luciferase analysis verified that miR-7641 directly bound to the 3’-UTR of USP7. In contrast, USP7 overexpression reduced autophagic activity and intensified inflammatory signaling. Notably, restoration of USP7 expression partially abolished the autophagy-promoting and inflammation-suppressive effects mediated by miR-7641.</p> Conclusions <p>miR-7641 promotes cytoprotective autophagy in macrophages and mitigates ox-LDL-induced inflammatory activation through direct repression of its downstream target USP7. The miR-7641/USP7/autophagy axis represents a newly characterized regulatory circuit in macrophage dysfunction during AS and may offer promising molecular targets for therapeutic intervention.</p>