Low-dose chronic exposure to hemin and kynurenine enhances metabolic adaptation in a colorectal cancer cell model.

Metabolic adaptation enables cancer cells to persist under fluctuating nutrient conditions and is a major driver of tumor progression, including colorectal cancer (CRC). The contribution of diet, such as red and processed meat, in tumor progression remains poorly understood. Here, we investigated how repeated exposure to hemin (HEM) and kynurenine (KYN), alone and in combination, shapes CRC cell metabolism under nutrient deprivation. Using respirometry and transcriptomics in 3D spheroids, we found that HEM and KYN induced distinct, context-dependent metabolic adaptations, differentially affecting glycolytic and oxidative energy pathways depending on nutrient availability. Co-exposure to HEM + KYN maintained energy production during glucose deprivation through enhanced lipid storage, revealing a mechanism by which red meat–derived metabolites reinforce metabolic plasticity. These findings demonstrate that red meat–derived metabolites modulate key bioenergetic pathways in a complementary manner and that their combined presence amplifies cancer cell adaptability, highlighting a potential mechanism linking diet to CRC progression.