To investigate the effect and mechanism of dihydroartemisinin (DHA) on ferroptosis in cervical cancer by the microRNA (miRNA)-346/Kruppel-like factor 14 (KLF14) axis.

In cell experiment, human cervical cancer Hela cells were treated and divided into several groups including cell normal control group (only HcerEpic cell), cell negative control group (only Hela cell), cell experimental group (Hela cell treated with 246.90 μmol·L^-1 DHA for 48 h), DHA+mimic NC group (transferred with mimic NC based on the cell experimental group), DHA+miR-346 mimic group (transfected with miRNA-346 mimic based on the cell experimental group), DHA+sh-NC group (transfected with sh-NC based on the cell experimental group) and DHA+sh-KLF14 group (transfected with sh-KLF14 based on the cell experimental group). In animal experiment, a xenograft tumor model was established by subcutaneous injection of Hela cells into 30 female BALB/c nude mice, which were then divided into the animal control group (gavaged with saline), animal experimental-L group (gavaged with 100 mg·kg^-1 DHA) and animal experimental-H group (gavaged with 200 mg·kg^-1 DHA), with 10 mice in each group. The relative expression level of miRNA-346 was detected by quantitative real-time polymerase chain reaction. The relative expression levels of KLF14 protein, glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) were measured by Western blot. Intracellular Fe²⁺ levels were detected using FerroOrange fluorescent probe. The apoptosis rate was determined by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay.

In cell experiment, the relative expression levels of miRNA-346 in the cell negative group and cell experimental group were 1.00±0.18 and 0.42±0.06, respectively; the relative expression levels of KLF14 mRNA were 1.00±0.17 and 2.22±0.32, respectively; the relative expression levels of KLF14 protein were 1.00±0.15 and 1.72±0.23, respectively; the relative fluorescence intensities of Fe²⁺ of cell negative control group, cell experimental group, DHA+mimic NC group, DHA+miRNA-346 mimic group, DHA+sh-NC group and DHA+sh-KLF14 group were 1.00±0.15, 4.86±0.81, 4.32±0.62, 3.12±0.57, 4.23±0.59 and 2.02±0.33, respectively; the relative expression levels of GPX4 protein were 1.00±0.17, 0.45±0.06, 0.48±0.07, 0.78±0.11, 0.44±0.06 and 0.59±0.08, respectively; the relative expression levels of SLC7A11 protein were 1.00±0.12, 0.37±0.05, 0.35±0.04, 0.86±0.12, 0.40±0.07 and 0.77±0.10, respectively; the cell proliferation rates were (100.00±3.65)%, (54.32±7.65)%, (56.32±8.02)%, (72.33±8.65)%, (52.32±9.23)% and (88.25±10.35)%, respectively; the apoptosis rates were (14.32±1.61)%, (61.33±8.25)%, (57.32±7.13)%, (32.44±5.37)%, (59.63±8.98)% and (23.88±3.49)%, respectively. Significant differences were observed in the aforementioned parameters when comparing the cell experimental group with the cell negative group, comparing the DHA + miRNA-346 mimic group with the DHA + mimic NC group, and comparing the DHA + sh-KLF14 group with the DHA + sh-NC group (P<0.01,P<0.001). In animal group, the tumor volumes in the animal control, experimental-L and experimental-H groups were (542.36±92.33), (402.85±92.28) and (295.52±60.56) mm³, respectively; the tumor masses were (1.55±0.33), (1.22±0.22) and(0.88±0.15)g, respectively; the relative positive levels of GPX4 were 1.00±0.18, 0.55±0.07 and 0.42±0.04, respectively; the relative positive levels of SLC7A11 were 1.00±0.16, 0.48±0.06 and 0.29±0.03, respectively. Significant differences were also detected between the animal experimenal-L, -H group and the animal control group (P<0.05, P<0.01, P<0.001).

DHA promotes ferroptosis in cervical cancer by the miRNA-346/KLF14 axis-mediated GPX4 signaling pathway.