HIF1α Integrates Lipogenic FASN and Glycolytic GLUT3 to Overcome intratumor Oxidative and Hypoxic Stress for Colorectal Cancer Metastasis

Background Colorectal carcinoma (CRC) is the third most prevalent cancer worldwide and a leading cause of cancer-related mortality, primarily due to its high propensity for metastasis. Despite therapeutic advancements, the molecular mechanisms by which intratumor hypoxia and oxidative stress contribute to malignancy remain poorly understood. Methods Gene expression profiles were analyzed across various stages of CRC (T1–T4) and metastatic CRC (mCRC). The role of hypoxia-inducible factor 1 alpha (HIF1α) was investigated in CRC cell lines and in vivo models to evaluate its impact on local tumor growth and lung metastasis. Mechanistic studies focused on HIF1α-mediated regulation of fatty acid synthase (FASN) and GLUT3 in the tumor microenvironment to promote CRC distant metastasis. Therapeutic targeting of HIF1α was assessed using echinomycin encapsulated in lipid nanoparticles. Results HIF1α was identified as a critical regulator enabling tumors to overcome intratumoral stress and proliferate in hypoxic regions. Activation of the IGF1/Insulin-AKT-mTOR pathway led to HIF1α accumulation, which, in turn, upregulated FASN and GLUT3 expression, mitigating oxidative and hypoxic stress. Elevated HIF1α levels were positively correlated with increased NRF2 activity in CRC cells, contributing to malignancy and metastatic potential. Targeting the HIF1α-FASN/GLUT3 axis with echinomycin-loaded lipid nanoparticles effectively inhibited tumor growth and abrogated lung metastases in preclinical models. Conclusions The IGF1/Insulin-HIF1α-FASN/GLUT3 signaling axis is a key driver of CRC progression and lung metastasis by counteracting oxidative stress and hypoxia. Therapeutic inhibition of HIF1α offers promising potential for mitigating CRC malignancy and preventing metastasis.