JAK3/STAT5A-dependent IL-8 regulation drives ESCC angiogenesis and is suppressed by dihydroartemisinin.

The tumor microenvironment plays a crucial role in tumor angiogenesis, yet the mechanism by which the microenvironment promotes tumor angiogenesis in esophageal squamous cell carcinoma (ESCC) is unclear. Here, transcriptomics revealed that IL-8 was the most significantly upregulated in HUVECs induced by ESCC cell supernatants, and the JAK3/STAT5A pathway was activated to regulate IL-8 during this process. Moreover, targeting JAK3 suppressed ESCC angiogenesis. Notably, dihydroartemisinin (DHA) directly targeted JAK3 and inhibited ESCC CM-induced HUVECs angiogenesis and the ESCC angiogenesis in vivo, similar to the clinical drugs Avastin or Apatinib. Mechanistically, STAT5A transcriptionally regulated IL-8, which could be inhibited by DHA. Besides, DHA inhibited ESCC angiogenesis through JAK3/STAT5A/IL-8 signaling in vivo and in vitro, and JAK3 blockade alleviated its effect. In conclusion, these findings demonstrate a critical role of the JAK3/STAT5A/IL-8 pathway in regulating ESCC angiogenesis, and DHA is an effective drug for targeting JAK3 against ESCC angiogenesis, providing a research basis and a new strategy for anti-ESCC angiogenesis therapy.