β-sitosterol inhibited hypoxia-related colorectal cancer metastasis by regulating HIF-1α/VEGF pathway

This study aimed to investigate how β-sitosterol (SIT) suppresses hypoxia-driven metastasis and angiogenesis in colorectal cancer.

We employed hypoxic colorectal cancer cells. The biological functions of SIT were assessed via in vitro assays for cell proliferation, migration, invasion, apoptosis and angiogenesis. A mouse model of colorectal cancer lung metastasis was constructed for grouped SIT intervention. Histopathology, immunofluorescence and Western blot were applied to detect the expression of key molecules.

In vitro, SIT dose-dependently inhibited proliferation, migration and invasion of hypoxic colorectal cancer cells and triggered apoptosis. Additionally, SIT markedly inhibited angiogenesis and reversed the epithelial-mesenchymal transition (EMT). In the lung metastasis mouse model, SIT reduced metastatic foci, relieved lung injury, reversed EMT, decreased CD11b⁺Gr1⁺ myeloid cell infiltration, and suppressed FAP, eNOS and DDAH₂ (angiogenesis-related factors). Further mechanistic studies revealed that SIT downregulated HIF-1α and VEGFA to mediate its anti-tumor actions.

Collectively, SIT blocked hypoxia-induced colorectal cancer metastasis and reversed the EMT through the HIF-1α/VEGF axis. Our findings offer new insights and potential therapeutic approaches for lung metastases from colorectal cancer.