Dihydroartemisinin Affects the Development 
of Rectal Cancer Through Inducing Ferroptosis 
via SREBP Cleavage Activator Protein/Sterol 
Regulatory Element-binding Protein Signaling

Background Rectal cancer has a high morbidity and mortality rate in China, endangering public health. Sterol regulatory element-binding protein cleavage-activating protein/sterol regulatory element-binding protein 1 (SCAP/SREBP1) signaling pathway is essential in tumor cell proliferation and apoptosis. Dihydroartemisinic (DHA) can exert anti-tumor effects by regulating tumor cell iron death. Purpose This study aimed to investigate the specific role and mechanism of DHA in inhibiting the proliferation of rectal cancer by inducing iron death through the SCAP/SREBP1 pathway. Methods Six groups were set: model group, SCAP/SREBP1 agonist group, SCAP/SREBP1 inhibitor group, 10%, 30%, and 50% DHA group, and randomly selected 10 SD rats with successful modeling in each group male rat. The pathological changes of the rectal tissue of rats were observed by staining, and cell viability, proliferation, and apoptosis were detected using cell counting kit-8 (CCK-8), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution, and flow cytometry. The levels of SCAP, SREBP, and glutathione peroxidase 4 (GPX4) were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR), and protein expressions of SCAP, SREBP, and GPX4 were detected by Western blot. Results The normal mice in the control group had a complete tissue structure, while the rectal tissue epithelial cells in the model group were irregular and deformed. Compared with the model group, the SCAP/SREBP1 agonist and 30% DHA group showed improvement, but/SREBP1 inhibitor group was more serious than the model group. DHA can be found to be negatively correlated with the proliferative activity of rectal cancer cell lines, and SCAP/SREBP1 can affect cell proliferation. The effect of DHA on rectal cancer cells was correlated with concentration and time dependence. When the concentration reaches 50%, the apoptosis rate reaches 20% and 25%, respectively, in 2 and 3 days. GSH decreased with the increase in DHA concentration. DHA can promote the expression of SCAP/SREBP1 and reduce the expression of GPX4, and SCAP/SREBP1 can also affect the expression of GPX4, and the decrease of SCAP/SREBP1 expression will lead to the increase of GPX4 expression. Conclusion DHA can inhibit the viability and promote apoptosis of rectal cancer cells by increasing the concentration of GSH and SCAP/SREBP1 signaling pathways. Therefore, DHA may become a new therapeutic method to inhibit rectal cancer cells.