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<p>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 <i>(circLDLR</i>), a CAF-derived circRNA, as a key factor associated with poor prognosis in colorectal cancer (CRC). During interactions between CAFs and CRC cells, <i>circLDLR</i> is packaged into exosomes and transferred to tumor cells, where it enhances proliferation and metastasis primarily by reducing susceptibility to ferroptosis. Mechanistically, <i>circLDLR</i> 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 <i>circLDLR</i> biogenesis within CAFs. Taken together, our study reveals that CAF-derived <i>circLDLR</i> confers ferroptosis resistance and promotes CRC progression via the GALNT14/SLC7A11 axis. Consequently, disrupting exosomal <i>circLDLR</i> transfer between CAFs and CRC cells may offer a promising therapeutic strategy for CRC.</p><p></p>

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

  • 期刊论文

  • 发表日期：

    2026年7月7日

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  • Jialu Guan,
  • Lingfeng Guo,
  • Shuo Ning,
  • Wenxi Zhao,
  • Tong Wang,
  • Jingjing Wang,
  • Zhen Qi,
  • Jingjing Huang,
  • Jianqi Wang,
  • Yuanfeng Gong,
  • Tiemin Pei,
  • Qinghui Meng,
  • Huayang Pan

摘要

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.