Molecular Mechanism and Research Progress of Sphingolipid Metabolism in Regulating Radiation-induced Apoptosis Using Pan-cancer Analysis.

Abstract

Radiotherapy stands as a cornerstone in cancer therapy, with nuclear DNA acknowledged as the principal target molecule for radiation-induced cellular demise or injury. Nonetheless, an expanding body of contemporary research elucidates the significant contri-bution of sphingolipids to radiation-induced cell death, particularly in modulating radiation-induced apoptosis. Radiation can instigate apoptosis through multiple pathways of sphin-golipid metabolism, encompassing the activation of ceramide synthase, acid sphingomyelin-ase, neutral sphingomyelinase, sphingosine-1-phosphate lyase, and sphingosine-1-phosphate phosphatase, and the inhibition of sphingosine kinase-1. The disruption of sphingolipid me-tabolism leads to an increase in pro-apoptotic sphingolipid ceramide and sphingosine and a decrease in anti-apoptotic sphingolipid sphingosine-1-phosphate, which ultimately triggers apoptosis in tumor cells. The diminished or absent response of sphingolipids to radiation rep-resents one of the contributors to radioresistance. In this context, numerous interventions tar-geting sphingolipids have been utilized to augment radiosensitivity in tumor tissue and miti-gate radiation-induced damage in normal tissue, demonstrating efficacy both in vitro and in vivo. Sphingolipids have also emerged as promising biomarkers for evaluating the response to radiotherapy in patients. Attaining a comprehensive understanding of sphingolipid metab-olism in radiation-induced apoptosis holds the potential to offer an effective strategy for en-hancing the efficacy of radiotherapy and mitigating resistance to such treatment.