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Tanshinone IIA, a multi-pharmaceutical compound from traditional Chinese herb, has been reported to have anti-hepatocarcinomic (HCC) properties through cell death induction. Apart from the typical p53-dependent pathway, mechanisms of the anti-carcinogenic role of Tanshinone remain scarce. In an effort to explore the mechanism behind Tanshinone IIA, we detected the upstream of the p53 and the potential novel pathway. Tanshinone IIA dose-dependently initiated HepG2 cell apoptosis and cell cycle arrest at the G1 checkpoint. In the miR30 family, only the transcription of miR30b was downregulated by Tanshinone IIA, which subsequently upregulated both the genomic and protein levels of p53. Further, we screened that PTPN11 and Tp53 are the two critical genomes involved in the pharmacology of Tanshinone IIA. Building upon LASAGNA-search and kinetics binding assay, p53 was found to be a potential transcription factor for PTPN11. Concomitant with the expression of p53, Tanshinone IIA stimulated both PTPN11 and its encoded protein SHP2. Inhibition miR30b attenuated the Tanshinone IIA-induced cytotoxicity, level of p53 and PTPN11 in HepG2 cells. Finally, the apoptotic molecules such as Bax/Bcl2, cleavage caspase 3 and the cell cycle regulation factors including p21, cyclin D1, and CDK6 were changed by Tanshinone IIA. Several cytotoxic endpoints induced by Tanshinone IIA were also checked in Hep3B cells. This study confirmed that Tanshinone IIA may induce hepatoma cell death through the miR30b-p53- PTPN11/SHP2 pathway. With regard to the complicated tumorigenesis of HCC and the multi-targets of Tanshinone IIA, our results propose developing Tanshinone IIA for clinic therapy and the interference of HCC.