The novel inhibitor of STARD7 induces ferroptosis through the NRF2/EGR1 pathway in TNBC
Objective To investigate the expression of StAR-related lipid transfer domain7(STARD7)in triple-negative breast cancer(TNBC)and its correlation with prognosis.To perform high-throughput screening for small molecule inhibitors of STARD7,and to study their effects on TNBC and their potential molecular mecha-nisms.Methods Bioinformatics analysis of the expression of STARD7 in breast cancer and its correlation with prognosis.Western blot(WB)and immunohistochemistry experiments were used to de-tect the expression of STARD7 in cell lines and clinical TNBC sam-ples.Targeting STARD7,molecular docking,in vitro protein purifica-tion,and in vitro molecular interaction experiments were conducted to screen and identify small molecule inhibitors of STARD7.The CCK8 assay was used to determine the survival rate of TNBC cells after 24 hours of treatment with control group(DMSO)and Lasiodin at concentrations of 1,2,5,10,and 20µmol/L to identify the optimal drug concentration.The cell death ratio of each group was de-termined by trypan blue and YO-PRO-1 staining,and the expression of apoptosis-and ferroptosis-related proteins was measured by Western blot.The expressions of mRNAs and proteins of NRF2,HO-1,KEAP1,and EGR1 were measured by RT-qPCR and Western blot,respectively.A TNBC xenograft model was established and randomly divided into control group,paclitaxel group(10 mg/kg),and Lasiodin group(10 mg/kg).After treatment,tumor volume and nude mouse body weight were measured,and biosafety was evalu-ated through HE staining.Results Bioinformatics analysis and in vitro experiments indicated that STARD7 was highly expressed in TNBC tissues and cells,and its high expression was negatively correlated with patient prognosis(P<0.05).High-throughput screen-ing identified Lasiodin as a small molecule inhibitor of STARD7.The inhibition of STARD7 by Lasiodin may induce ferroptosis in TN-BC cells by regulating the expression of proteins related to the downstream NRF2/EGR1 pathway,along with apoptosis and necrosis.In vivo experiments demonstrated that Lasiodin inhibited the growth of tumors(P<0.05)without observable significant toxic side ef-fects.Conclusion STARD7 may play a significant regulatory role in the progression of TNBC,and Lasiodin,as its small molecule inhibitor,suggesting that STARD7 and Lasiodin could potentially serve as a target and novel drug,respectively,for the treatment of TNBC.
STARD7Lasiodintriple-negative breast cancermolecular dockingsmall molecule inhibitorferroptosisapop-tosis
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