Industrial additive and dietary fiber inulin induces tumor-selective necrotic death via mitochondrial lipid peroxidation involving MYC and YAP.

Inulin, as a prebiotic fiber and an industrial additive, has been shown to regulate gut and small intestinal microbiomes for health, but non-microbiota-dependent cellular pathways remain unclear. Here we aim to determine how the natural polysaccharide inulin reshapes metabolic stress responses, especially in colon cancer cells. In tumor cells treated with inulin, oxidized lipids accumulated in the perimitochondrial region and were accompanied by mitochondrial fragmentation, Golgi dispersion, endoplasmic reticulum (ER) disorganization, lysosomal remodeling, increased mitochondrially encoded cytochrome c oxidase II (MTCO2), and nuclear p21, indicating organelle stress coupled to metabolic reprogramming. Non-malignant cells showed elevated lipid peroxidation but limited necrotic death, consistent with greater metabolic tolerance. YAP/MYC inhibition increased inulin sensitivity. Importantly, ataxia telangiectasia and Rad3-related (ATR) supported stress adaptation, particularly in normal cells. Additionally, inulin decreased nuclear active MYC and YAP and enhanced nuclear androgen receptor (AR). Network pharmacology identified that inulin is against colon cancer by the AR-related hub gene PTGS2 (prostaglandin G/H synthase-2) and it was validated by a synergistic combination with progesterone. Thus, inulin triggers tumor-selective metabolic stress and disrupts adaptive MYC/YAP, providing a rationale for metabolism-based precision cancer therapy.