Exosomal microRNAs (miRNAs) have emerged as important regulators of chemotherapy response. This study aimed to investigate whether exosomal miR-4443 is associated with cisplatin resistance in breast cancer and to explore its potential relationship with ferroptosis. Exosomes were isolated from cisplatin-sensitive and cisplatin-resistant breast cancer tissues, as well as from cisplatin-sensitive (MCF-7-S) and cisplatin-resistant (MCF-7-R) breast cancer cell lines. Exosomes were characterized by transmission electron microscopy, nanoparticle tracking analysis, and detection of canonical exosomal markers. miR-4443 expression was quantified by qRT-PCR. Cell viability, colony formation, iron accumulation, and reactive oxygen species (ROS) levels were assessed following cisplatin treatment and modulation of miR-4443 expression. Ferroptosis-related responses were evaluated using pharmacological inducers and inhibitors. The effects of miR-4443 on cisplatin response were further examined in a subcutaneous xenograft model. Exosomal miR-4443 levels were significantly higher in cisplatin-resistant breast cancer tissues and cell lines compared with cisplatin-sensitive counterparts. Exosomes derived from cisplatin-resistant samples transferred miR-4443 to sensitive cells and attenuated cisplatin-induced growth inhibition. Modulation of miR-4443 expression altered cellular sensitivity to cisplatin and ferroptosis-related stress, accompanied by changes in iron accumulation, ROS levels, and expression of the ferroptosis suppressor FSP1. In vivo, miR-4443 overexpression reduced the antitumor efficacy of cisplatin and was associated with increased FSP1 expression in tumor tissues. These findings suggest that exosomal miR-4443 is associated with cisplatin resistance in breast cancer and may contribute to this phenotype, at least in part, through modulation of ferroptosis-related pathways. Targeting miR-4443 or modulating ferroptosis-related pathways may represent a promising strategy to enhance cisplatin sensitivity; however, further mechanistic dissection and larger-scale clinical validation will be required before translational application. (XMSQ2026046)
Wang et al. (Sun,) studied this question.