Exosomal miR-4443 promotes cisplatin resistance in non-small cell lung carcinoma by regulating FSP1 m6A modification-mediated ferroptosis

Aims: Exosomal transfer of miRNAs affects recipient cell proliferation and chemoresistance. Here, we aimed to investigate the role of exosomal miRNAs in controlling cisplatin resistance in non-small cell lung carcinoma (NSCLC). Main methods: Paired tumor and normal tissue-derived exosomes were collected from NSCLC patients with low or high responsiveness to cisplatin treatment. The results showed that the microRNA-4443 (miR-4443) level was upregulated in cisplatin-resistant NSCLC tumor tissue-derived exosomes compared with cisplatin-sensitive tissuederived exosomes. Cisplatin-resistant cells (A549-R) were generated from the parental cells (A549-S). Resistant exosomes conferred cisplatin resistance by transferring miR-4443 to sensitive cells. Moreover, overexpression of miR-4443 inhibited FSP1-mediated ferroptosis induced by cisplatin treatment in vitro and enhanced tumor growth in vivo. Key findings: Through bioinformatics analysis and luciferase assays, METTL3 was confirmed as a direct target gene of miR-4443. Further mechanistic analysis showed that miR-4443 regulated the expression of FSP1 in an m6A manner via METLL3. Significance: Our findings provide more in-depth insight into the chemoresistance of NSCLC and support the therapeutic potential of targeting ferroptosis.

Automated summary

The study revealed the role of exosomal miRNA miR-4443 in controlling cisplatin resistance in NSCLC, showing that miR-4443 confers cisplatin resistance by transferring through exosomes and enhances tumor growth by regulating the FSP1-mediated ferroptosis pathway. Additionally, METTL3 was identified as a direct target gene of miR-4443, providing insights into the therapeutic potential of targeting ferroptosis in NSCLC chemoresistance.