Radiation induced dermatitis by increasing triglyceride levels to induce autophagy and inhibit the PI3K/Akt/mTOR signaling pathway

Radiodermatitis (RD) is the primary acute adverse effect experienced by patients receiving radiotherapy (RT) for head and neck cancer (HNC). This study aimed to investigate the correlation between triglyceride (TG) levels and the severity of RD, as well as the underlying mechanisms involved. Data were collected from 248 patients with locally advanced HNC treated with intensity-modulated radiation therapy (IMRT). Clinical characteristics and blood profiles prior to RT were collected. After RT, RD severity was assessed. A binary logistic regression analysis was used to determine risk factors. Mouse models of RD were established by administering radiating at a dose of 9 Gy over two consecutive days. TG levels in the mice and cells were quantified using an automatic biochemical analyzer and a TG assay kit, respectively. Cell viability was detected by the Cell Counting Kit-8 (CCK-8) assay, while apoptotic cell percentages were measured via flow cytometry. Western blotting assay was used to analyze the protein levels in the cells of interest. The TG level was the sole independent risk factor for grade 3 or higher (grade 3+) RD. Radiation was found to increase the TG content in both mouse blood and skin cells. Skin cells with high TG contents presented more severe radiation-induced damage when the radiation dose administered was 9 Gy over two consecutive days. The administration of 200 µmol/L palmitic acid (PA) or 2 Gy radiation independently did not affect HaCaT cell proliferation or apoptosis rates. Their combination was shown to induce skin cell injury. Mechanistically, autophagy was excessively activated. Furthermore, the protein concentrations of phospho-PI3K, phospho-Akt, and phospho-mTOR were notably decreased. TGs are crucially involved in the development of RD. Increased TG levels after radiation treatment suppress the PI3K/Akt/mTOR pathway, induce autophagy, and exacerbate RD.