Jianpi Jiedu formula modulates glutamine metabolism to inhibit colorectal cancer liver metastasis.

[BACKGROUND] Liver metastasis is a primary cause of mortality in colorectal cancer (CRC) patients and significantly impacts patient prognosis. Jianpi Jiedu formula (JPJDF), a traditional Chinese medicine composed of six herbal ingredients, demonstrates clinically proven anti-metastatic efficacy against CRC.

[PURPOSE] This study investigates the therapeutic potential of JPJDF for CRC metastasis and elucidates its regulatory mechanisms targeting glutamine metabolism.

[METHODS] Mass spectrometry identified blood-absorbed anticancer bioactive compounds in JPJDF and evaluated their pharmacokinetics. Energy metabolomics compared metabolic profiles between healthy liver and CRC liver metastatic tissues. A murine CRC liver metastasis model was established. Anti-metastatic effects were assessed via small-animal in vivo imaging and tumor volumetry. Glutamine/glutamate assays, immunofluorescence, flow cytometry, and molecular biology techniques explored JPJDF's mechanistic role in glutamine metabolism regulation and immune modulation across in vivo and in vitro systems.

[RESULTS] Following administration, bioactive compounds derived from JPJDF with anticancer activity were detected in the systemic circulation. JPJDF dose-dependently suppressed primary tumor growth and distant metastasis. Liver metastasis exhibited pronounced glutamine metabolic reprogramming. JPJDF inhibited metastasis by modulating glutamine metabolism in metastatic niches through the YTHDF1/GID8 axis. Mechanistically, this axis mediates SLC1A3/GLS pathway suppression, reducing glutamine utilization by CRC cells. Furthermore, comprehensive immunophenotyping of metastatic liver lesions revealed that JPJDF effectively reversed the immunosuppressive TME, characterized by reduced macrophage infiltration and increased abundance of T lymphocytes and mature dendritic cells.

[CONCLUSION] JPJDF suppresses CRC metastasis by targeting glutamine metabolism via the YTHDF1/GID8 axis and by remodeling the immunosuppressive tumor microenvironment, highlighting its potential as an adjunct therapeutic strategy for metastatic CRC.