N6-methyladenosine-modified circLPAR3 drives docetaxel resistance in prostate cancer by suppressing ferroptosis through the PCBP2/CHAC1 axis

Epigenetic mechanisms represented by N6-methyladenosine (m⁶A) modifications and circular RNAs (circRNAs) regulate chemotherapy resistance in prostate cancer (PCa). Here, we stuided the role of m⁶A-modified circLPAR3 in assisting docetaxel (DTX) resistance in PCa and the mechanism of its regulatory function. The expression of circLPAR3 was higher in all three drug-resistant cell lines than in the corresponding parental cell lines and was mainly localized in the cytoplasm. The m⁶A modification and stability enhancement of circLPAR3 by the METTL3/IGF2BP2 axis was primarily determined by expression assays, stability assays, and mass spectrometry. Functionally, circLPAR3 reduced the sensitivity of PCa cells to DTX and promoted PCa proliferation in a DTX environment. In addition, circLPAR3 reduced cytotoxicity by inhibiting the DTX-induced ferroptosis effect. Mechanistically, circLPAR3 downregulated the expression of CHAC1, an emerging driver of ferroptosis. PCBP2 was identified as a mediating RNA-binding protein between circLPAR3 and CHAC1. On the one hand, it shares a very high binding phase with circLPAR3 without interfering with each other's expression; on the other hand, it increases mRNA stability by binding to the 3' UTR of CHAC1, which is interfered by circLPAR3. In conclusion, m⁶A-modified circLPAR3 inhibits CHAC1 expression by competitively binding to PCBP2, ultimately conferring docetaxel resistance to PCa.