MiR-144-3p enhances cisplatin sensitivity in triple-negative breast cancer by targeting SLC7A11 to induce ferroptosis.

BACKGROUND

Triple-negative breast cancer (TNBC) is an aggressive subtype in which resistance to cisplatin (cis-diamminedichloroplatinum II, CDDP) limits therapeutic efficacy, and ferroptosis has emerged as a key determinant of chemotherapy response. This study investigated the role of miR-144-3p in regulating CDDP sensitivity in TNBC and its underlying mechanism.

METHODS

MiR-144-3p expression was analyzed in TNBC tissues from CDDP-sensitive and -resistant patients. CDDP-resistant cell lines (MDA-MB-231/CDDP and BT-549/CDDP) were established by stepwise CDDP exposure and validated by increased IC50 values. Gain- and loss-of-function assays were performed using miR-144-3p mimic, si-SLC7A11, and SLC7A11 overexpression plasmids. Cell viability, clonogenic survival, and apoptosis were assessed by CCK-8, colony formation, and flow cytometry. Ferroptosis was evaluated by measuring lipid peroxidation (C11-BODIPY), ROS, GSH, Fe2+ levels, and GPX4 expression. Targeting of SLC7A11 by miR-144-3p was confirmed by dual-luciferase reporter assay and expression analysis. A xenograft model was used to assess tumor growth, SLC7A11 expression, and ferroptosis-related indicators in vivo.

RESULTS

MiR-144-3p was significantly downregulated in CDDP-resistant TNBC tissues and cells. Its restoration enhanced CDDP sensitivity and was associated with increased ferroptotic features, as evidenced by increased lipid peroxidation and ROS, decreased GSH, elevated Fe2+ levels, and reduced GPX4 expression. Mechanistically, miR-144-3p directly targeted SLC7A11. Rescue experiments showed that SLC7A11 overexpression attenuated ferroptosis and partially reversed CDDP sensitization. In vivo, miR-144-3p overexpression suppressed tumor growth, reduced SLC7A11 expression, and enhanced ferroptotic features.

CONCLUSION

Our findings suggest that miR-144-3p enhances CDDP sensitivity in TNBC, at least in part, through regulation of the SLC7A11-mediated ferroptosis pathway, identifying a novel regulatory axis with therapeutic potential.