Fatty acid-induced lipid accumulation promotes radiosensitization in Huh7 hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality, represents a substantial global health burden, and the therapeutic efficacy of radiotherapy remains highly variable among patients with the condition. Metabolic alterations, particularly in lipid metabolism, may modulate radiosensitivity, although the underlying mechanisms are not fully understood. The present study investigated the impact of fatty acid uptake on radiosensitivity in HCC using the Huh7 cell line. Oleic acid (OA), a monounsaturated fatty acid, was used to induce intracellular lipid accumulation. Flow cytometry analyses revealed that OA treatment (1 mM; 18 h) considerably increased lipid content without inducing cytotoxicity. When combined with X-ray irradiation (10 Gy), OA pretreatment considerably enhanced cell death, as indicated by an increased proportion of propidium iodide-positive cells. This effect was associated with elevated levels of lipid hydroperoxides and reactive oxygen species, suggesting oxidative stress-mediated mechanisms. Furthermore, mRNA expression analyses revealed marked upregulation of ChaC glutathione specific γ-glutamylcyclotransferase 1, a gene involved in glutathione degradation and ferroptosis, in OA-treated cells. The expression levels of glutathione peroxidase 4 and glutamate-cysteine ligase catalytic subunit, key antioxidant defense genes, were also upregulated by OA and irradiation. These findings indicate that OA-induced lipid accumulation sensitized HCC cells to radiation through enhanced oxidative stress and lipid peroxidation. However, as the present study was based on an in vitro model using a single cell line, the potential clinical relevance of these findings remains speculative and requires further validation in in vivo models and clinical studies.