Modified Fuzheng Yiliu Decoction chemosensitizes colorectal cancer by inhibiting cancer stem cell metabolism and stemness through CAV1/ZNF460/GRP78 signaling.

BACKGROUND

Cancer stem cells (CSCs) drive colorectal cancer (CRC) therapeutic resistance through metabolic reprogramming, particularly aerobic glycolysis. Strategies simultaneously targeting CSC metabolism and stemness remain limited.

PURPOSE: To evaluate the chemosensitizing effect of Modified Fuzheng Yiliu Decoction (MFYD) in CRC and elucidate the underlying mechanisms involving CSC inhibition.

STUDY DESIGN AND METHOD: An AOM/DSS-induced murine CRC model was employed to assess the chemosensitizing effects of MFYD on 5-fluorouracil (5-FU). Network pharmacology, transcriptomic sequencing, and molecular experiments were used to identify key targets and mechanisms. Clinical efficacy was evaluated in 120 high-risk stage II/III CRC patients, with patient-derived stem-like spheroids (PDSLS) for mechanistic validation.

RESULTS

MFYD significantly suppressed colorectal tumorigenesis and synergistically chemosensitized 5-FU with little toxicity. MFYD dose-dependently reduced CD133+CD44+ CSC populations and downregulated stemness-associated proteins (LRP5, β-catenin, CD44). Metabolic analysis revealed that MFYD preferentially inhibited aerobic glycolysis in CD133+CD44+ CSC-like cells versus CD133-CD44- non-stem cells. Mechanistically, MFYD suppressed CSC stemness and glycolysis by targeting CAV1, which promotes ZNF460 nuclear translocation to activate GRP78 transcription. Notably, CAV1 overexpression reversed these inhibitory effects of MFYD. Clinically, MFYD combined with XELOX chemotherapy significantly improved 5-year disease-free survival (P=0.045) and overall survival (P=0.042), while reducing circulating tumor cell counts (P=0.028). PDSLS experiments confirmed that MFYD suppressed stemness markers and glycolytic metabolism via CAV1/ZNF460/GRP78.

CONCLUSION

Our findings delineate a novel CSC signaling of CAV1/ZNF460/GRP78 in mediating chemoresistance of CRC, and support MFYD integration into standard chemotherapy to improve clinical outcomes.