Shikonin inhibits multiple tumor malignant phenotypes and is associated with Hedgehog pathway downregulation in lung adenocarcinoma.

Shikonin (SH) is a natural component extracted from Lithospermum erythrorhizon Siebold & Zucc, a traditional Chinese medicine, which has been shown to have anti-tumor effects in recent years. However, the specific mechanism behind these effects has not yet been reported. Thus, it is important to clarify the specific anti-tumor mechanism of SH and then develop it as a new anti-tumor drug. The objective of this study was to investigate the anti-tumor effect of SH on lung adenocarcinoma and its associated mechanism. SH was co-cultured with A549 cells, and the effects of SH on tumor-related phenotypes were evaluated via methods such as CCK-8, transwell, and TUNEL assays. Transcriptomics was performed to investigate the expression profile of SH-regulated genes as well as the signaling pathways involved. Moreover, the anti-tumor effect of SH was verified using a mouse lung cancer xenograft model. SH inhibited the proliferation, metastasis, and invasion of A549 cells, promoted apoptosis, and regulated the expression of malignant phenotype-related markers. The transcriptomic analysis indicated that SH regulated the expression of various malignant phenotype-related mRNAs and inhibited the Hedgehog pathway activation. Furthermore, SH improved the general state of lung cancer-bearing mice, suppressed the growth of transplanted tumors, and inhibited the expression of tumor markers. The findings of this study are the first to reveal the anti-lung adenocarcinoma effect of SH from multiple perspectives-namely, increasing cancer cell apoptosis and suppressing cancer cell proliferation, metastasis, and invasion by inhibiting the Hedgehog pathway activation.