〔Abstract〕 Objective To investigate the effect and mechanism of Src homology 2 domain-containing protein tyrosine phosphatase inhibitor PHPS1 on atherosclerotic plaque vulnerability in ApoE knockout mice, and to provide a new idea for the study of atherosclerosis.Methods Sixteen 8-week-old ApoE-/-mice were randomly divided into control group and PHPS1 group. The aortic root was fixed with formalin and sectioned. The collagen and macrophage contents in the plaque were evaluated by Movat and Sirius red staining. The activity of ERK and the expression of MMP-9 in the descending aorta were detected by Western blot.Results The plaque area(0. 52 ± 0. 05),(0. 31 ± 0. 03), collagen content(0. 062 ± 0. 013),(0. 136 ± 0. 022) and macrophage cell ratio(0. 799 ±0. 031),(0. 621 ± 0. 043) were different between PHPS1 group and control group(P<0. 01). The results of western blot showed that PHPS1 inhibited the activity of ERK and decreased the protein expression of MMP-9(P<0. 01).Conclusion PHPS 1, an inhibitor of SHP-2, can inhibit ERK activity and decrease the expression of MMP-9, thus reducing the degradation of collagen in fibrous cap and stabilizing vulnerable atherosclerotic plaque.