Head and neck cancer (HNC) is the sixth most common human malignancy with a global incidence of 650,000 cases per year. Radiotherapy (RT) is commonly used as an effective therapy to treat tumours as a definitive or adjuvant treatment. Despite the substantial advances in RT contouring and dosage delivery, patients suffer from various radiation-induced complications, among which are toxicities to the nervous tissues in the head and neck area. Radiation-mediated neuropathies manifest as a result of increased oxidative stress-mediated apoptosis, neuroinflammation and altered cellular function in the nervous tissues. Eventually, molecular damage results in the formation of fibrotic tissues leading to susceptible loss of function of numerous neuronal substructures. Neuropathic sequelae following irradiation in the head and neck area include sensorineural hearing loss, alterations in taste and smell functions along with brachial plexopathy, and cranial nerves palsies. Numerous management options are available to relieve radiation-associated neurotoxicities notwithstanding treatment alternatives that remain restricted with limited benefits. In the scope of this review, we discuss the use of variable management and therapeutic modalities to palliate common radiation-induced neuropathies in head and neck cancers.

Although once considered as structural components of eukaryotic biological membranes, research in the past few decades hints at a major role of bioactive sphingolipids in mediating an array of physiological processes including cell survival, proliferation, inflammation, senescence, and death. A large body of evidence points to a fundamental role for the sphingolipid metabolic pathway in modulating the DNA damage response (DDR). The interplay between these two elements of cell signaling determines cell fate when cells are exposed to metabolic stress or ionizing radiation among other genotoxic agents. In this review, we aim to dissect the mediators of the DDR and how these interact with the different sphingolipid metabolites to mount various cellular responses.

Patients undergoing radiotherapy (RT) for various tumors localized in the abdomen or pelvis often suffer from radiation nephrotoxicity as collateral damage. Renal podocytes are vulnerable targets for ionizing radiation and contribute to radiation-induced nephropathies. Our prior work previously highlighted the importance of the lipid-modifying enzyme sphingomyelinase acid phosphodiesterase like 3b (SMPDL3b) in modulating the radiation response in podocytes and glomerular endothelial cells. Hereby, we investigated the interplay between SMPDL3b and oxidative stress in mediating radiation injury in podocytes. We demonstrated that the overexpression of SMPDL3b in cultured podocytes (OE) reduced superoxide anion generation and NADPH oxidase activity compared to wild-type cells (WT) post-irradiation. Furthermore, OE podocytes showed downregulated levels of NOX1 and NOX4 after RT. On the other hand, treatment with the NOX inhibitor GKT improved WTs' survival post-RT and restored SMPDL3b to basal levels. in vivo, the administration of GKT restored glomerular morphology and decreased proteinuria in 26-weeks irradiated mice. Taken together, these results suggest a novel role for NOX-derived reactive oxygen species (ROS) upstream of SMPDL3b in modulating the response of renal podocytes to radiation.