Cancer‐Associated Fibroblasts Promote Glucose Metabolic Reprogramming and Progression of Triple‐Negative Breast Cancer via Exosomal circFAD104‐Mediated Intercellular Communication

Abstract

ABSTRACT Triple‐negative breast cancer (TNBC) is characterized by high metastatic tendency and poor prognosis, largely driven by dynamic crosstalk between cancer cells and the tumor microenvironment (TME). Cancer‐associated fibroblasts (CAFs) are a major component of the TME, yet their functional contributions to TNBC progression remain incompletely understood. In this study, we isolated exosomes from patient‐derived CAFs and normal fibroblasts (NFs), and profiled their circRNA content using RNA sequencing. circFAD104 was significantly enriched in CAFs and their derived exosomes, with elevated stromal expression confirmed by qRT‐PCR and in situ hybridization (ISH). PKH26 labeling demonstrated that CAF‐derived exosomes efficiently deliver circFAD104 to TNBC cells, where it enhances cancer stemness, metastasis, and glycolysis. Mechanistically, circFAD104 acts as a molecular scaffold to promote the interaction between the E3 ubiquitin ligase MARCHF8 and its substrate PGM1, facilitating MARCHF8‐mediated K48‐linked ubiquitination and subsequent proteasomal degradation of PGM1. Loss of PGM1 redirects glucose flux from glycogen synthesis toward glycolysis, thereby fueling tumor progression. Clinically, high circFAD104 levels were correlated with poorer overall survival in breast cancer patients. These findings uncover a CAF‐exosomal circFAD104 axis that reprograms glucose metabolism to drive TNBC progression via the circFAD104/MARCHF8/PGM1 pathway, highlighting its potential as a stroma‐targeted biomarker and prognostic predictor.