Background: Aortic dissection refers to the separation of aortic media and extension along the long axis to form the true and false chambers of the aortic wall. 65-70% of the patients died of cardiac tamponade, arrhythmia, dissection rupture, etc. At present, echocardiography, computed tomography angiography (CTA), etc. are the main diagnosis tools for aortic dissection. To date, there is no rapid serum molecular marker that can be used for differential diagnosis and risk assessment.Objectives: To screen serum molecular markers systematically amid aortic dissection and acute coronary syndrome and to preliminarily identify the pathogenesis of acute aortic dissection.Methods: Related disputes cases of all hospitals were statistically analyzed for the AAD medical disputes ratio, early death ratio and misdiagnosis ratio from the database of Guangdong Province Medical Disputes Coordination Committee from 2013 to 2017. Serum and Aortic tissues samples were respectively quantified by iTRAQ and label-free analysis, further validated by ELISA and protein verified by immunofluorescence and Western blot from AAD and control patients enrolled from the Zhujiang Hospital of Southern Medical University and Guangdong Province people's Hospital from 2016 to 2018.Results: AAD cases ratio accounted for 15.29% in all 150 cardiovascular disputes, 59.26% in all cardiovascular death less than 24 h, and 88.89% in the patients who remained undiagnosed at the time of death, 84 proteins (66 and 18 upregulated and downregulated, respectively) were identified by iTRAQ and 16 proteins (9 and 7 upregulated and downregulated, respectively) by Label-free. Nine proteins (Lumican, FGL1, PI16, MMP9, FBN1, MMP2, VWF, MMRN1, and PF4) related to the pathogenesis of aortic dissection were identified by David /Ease and String techniques as candidate biomarkers for verification test. Four proteins (Lumican, FGL1, PI16, and MMP9) were found to be statistically different after ELISA verification. The expression of FGL1, PI16, and MMP9 proteins was pathologically significantly increased except for Lumican. Histologically, TGF-beta 1, alpha-SMA, and Collagen1 were also significantly higher in the aortic group.Conclusion: Lumican, FGL1, PI16, and MMP9 may be potential biomarkers in AAD patients, and the Lumican-mediated TGF-beta 1 pathway is likely to be involved in the pathogenesis of aortic dissection.