Abstract: AIM:To investigate the effect of phosphatase and tensin homolog deleted on chromosome ten (PTEN) on ox-LDL-induced inflammatory cytokine levels in macrophages and its underlying mechanism. METHODS: The constructed pcDNA3.1(+)-PTEN (rPTEN) recombinant vector and PTEN siRNA were transfected into RAW 264.7 followed by stimulation with 50 mg/L ox-LDL for 24 h. Real-time PCR (RT-PCR) and Western blotting were used to analyze the expression levels of PTEN mRNA and protein. ELISA was used to detect the inflammatory cytokine levels of TNF-α and IL-6. The expression level of TLR4-NF-κB and its underlying mechanism were also explored. RESULTS: Overexpression of PTEN enhanced ox-LDL-induced inflammatory cytokine levels of TNF-α and IL-6, whereas its silencing attenuated this progress. PTEN upregulation increased the expression of ox-LDL-induced TLR4 and its downstream p65 NF-κB. However, silencing PTEN expression with PTEN siRNA significantly decreased ox-LDL-triggered activation of TLR4-NF-κB signaling. Further mechanism analysis demonstrated that preconditioning with PI3K/AKt specific inhibitor LY294002 (1 μmol/L) dramatically augmented PTEN silencing-decreased activation of TLR4-NF-κB pathway, accompanied by the increase in TNF-α and IL-6 levels. CONCLUSION: PTEN may regulate macrophage inflammatory by PI3K/AKt-TLR4-NF-κB pathway. This study thus provides a potential target for the treatment of cardiovascular diseases.