CAFs-derived exosomes inhibits ferroptosis via GALNT14-mediated O-GalNAcylation of SLC7A11 in colorectal cencer

In the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs), the dominant stromal component, actively shape cancer progression through exosomal communication. Here, we identify hsa_circ_0003892 ( circLDLR ), a CAF-derived circRNA, as a key factor linked to poor prognosis in colorectal cancer (CRC). During CAF–CRC interaction, circLDLR is packaged into exosomes and transferred to tumor cells, enhancing proliferation and metastasis largely by reducing ferroptosis susceptibility. Mechanistic exploration revealed that circLDLR stabilizes Polypeptide N-Acetylgalactosaminyltransferase 14 (GALNT14) by shielding it from ZNRF2-mediated ubiquitin degradation, leading to elevated GALNT14 protein levels. Elevated GALNT14 promotes O-GalNAcylation of Solute Carrier Family 7 Member 11 (SLC7A11) at Ser26, facilitating its membrane localization, thereby suppressing ferroptosis in CRC cells. Moreover, EIF4A3, an RNA-binding protein (RBP), contributes to circLDLR biogenesis within CAFs. Taken together, our study reveals that CAFs-derived circLDLR can confer ferroptosis resistance and boost the progression of CRC, which are mainly dependent on increasing the stability of GALNT14 and enhancing O-GalNAcylation-mediated membrane localization of SLC7A11, thus, disrupting circLDLR transfer between CAFs and CRC cells may offer a promising approach for CRC therapy.