CAF-derived exosomes inhibit ferroptosis via GALNT14-mediated O-GalNAcylation of SLC7A11 in colorectal cancer.

In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs)-the dominant stromal component-actively shape cancer progression through exosome-mediated communication. Here, we identify hsa_circ_0003892 (circLDLR), a CAF-derived circRNA, as a key factor associated with poor prognosis in colorectal cancer (CRC). During interactions between CAFs and CRC cells, circLDLR is packaged into exosomes and transferred to tumor cells, where it enhances proliferation and metastasis primarily by reducing susceptibility to ferroptosis. Mechanistically, circLDLR stabilizes Polypeptide N-Acetylgalactosaminyltransferase 14 (GALNT14) by protecting it from ZNRF2-mediated ubiquitination and degradation. This stabilization promotes the O-GalNAcylation of Solute Carrier Family 7 Member 11 (SLC7A11) at Ser26, facilitating its membrane localization and thereby suppressing ferroptosis in CRC cells. Additionally, we demonstrate that the RNA-binding protein EIF4A3 facilitates circLDLR biogenesis within CAFs. Taken together, our study reveals that CAF-derived circLDLR confers ferroptosis resistance and promotes CRC progression via the GALNT14/SLC7A11 axis. Consequently, disrupting exosomal circLDLR transfer between CAFs and CRC cells may offer a promising therapeutic strategy for CRC. Schematic diagram of the mechanism by which CAF-derived circLDLR promotes CRC progression through ferroptosis regulation. In the tumor microenvironment, CAFs highly express circLDLR, whose biogenesis is facilitated by EIF4A3-mediated splicing of LDLR pre-mRNA. circLDLR is then packaged into exosomes and transferred to CRC cells. Within CRC cells, circLDLR specifically binds to GALNT14 and inhibits its ubiquitination and degradation mediated by ZNRF2, thereby enhancing GALNT14 protein stability. Stabilized GALNT14 promotes O-GalNAcylation of SLC7A11 at Ser26, facilitating its membrane localization and increasing cystine uptake. The elevated cystine metabolism enhances GSH production, thereby suppressing ferroptosis and driving CRC cell proliferation and progression.