Dihydroartemisinin induces pyroptosis by promoting the AIM2/caspase-3/DFNA5 axis in breast cancer cells

Background: Breast cancer is a complex disease. Recent research has examined the anticancer effects of dihydroartemisinin (DHA) on breast cancer. However, the molecular mechanism of the antitumour effect of DHA is unclear. Methods: MCF-7 and MDA-MB-231 cell lines were used for in vitro research. BALB/c nude mice were used to establish breast cancer xenografts. The mRNA and protein levels were analysed by qRT-PCR and western blotting, respectively. Flow cytometry was performed to examine cell apoptosis. ELISA kits were used to evaluate the production of interleukin-1 beta (IL-1 beta) and IL-18. LDH and ATP release were individually measured with the corresponding kits. A colony formation assay was used to examine the proliferation of breast cancer cells. Results: DHA inhibited proliferation and induced pyroptosis in breast cancer cells. Mechanistically, DHA activated the expression of absent in melanoma 2 (AIM2), caspase-3 and gasdermin E (DFNA5). In addition, AIM2 promoted DFNA5 expression by activating caspase-3. Knockdown of AIM2 and DFNA5 significantly enhanced breast cancer cell resistance to DHA. In vivo experiments showed that the tumorigenicity of breast cancer cells was significantly suppressed by DHA. Moreover, the AIM2/caspase-3/DFNA5 axis was activated by DHA and then induced pyroptosis. Conclusions: Our findings indicate that DHA inhibits tumorigenesis by inducing pyroptosis in breast cancer cells, highlighting a promising therapeutic strategy for breast cancer.