Targeting Polyamine Metabolism in Colorectal Cancer: Apigenin Dismantles the HIF-1α/SMOX Positive Feedback Loop to Suppress Tumor Progression.

Tumor microenvironments, particularly hypoxia and inflammation, heavily influence colorectal cancer (CRC) pathogenesis by altering polyamine metabolism. Identifying natural compounds targeting these vulnerabilities remains critical. Integrating untargeted metabolomics, network pharmacology, and a human endogenous metabolite library screen, we identified apigenin (API) as a potent anti-CRC candidate. API significantly inhibited the proliferation, migration, and invasion of RKO and HCT116 cells in vitro and suppressed xenograft tumor growth in vivo. Crucially, high-throughput screening revealed that polyamines rescued CRC cells from API-induced cytotoxicity. Mechanistically, API exerts its effects by dismantling a newly identified HIF-1α/SMOX positive feedback loop. In CRC, HIF-1α transcriptionally activates spermine oxidase (SMOX), while SMOX-driven polyamine metabolism fuels the TLR4/MyD88 inflammatory cascade to continuously stabilize HIF-1α. API acts as a "circuit breaker" for this axis, significantly reducing the spermidine/spermine ratio and downregulating inflammatory signaling. Ultimately, API effectively remodels polyamine metabolism and suppresses CRC progression by disrupting the HIF-1α/SMOX and TLR4/MyD88 pathways, offering a novel metabolic mechanism for API in CRC therapy.