FAT-5/SCD5-mediated lipid localization in lysosomes alleviates gamma radiation injury in Caenorhabditis elegans

Accidental internal or external exposure to gamma radiation can cause severe injury to the human body. The identification of an effective medication target has become particularly important for the treatment of radiation-induced injury. In this work, Caenorhabditis elegans was found to tolerate high-dose radiation when exposed to an extremely low-temperature environment (at 4 °C) for 4 h before irradiation. Experimental confirmation revealed that metabolites excreted by C. elegans targeted the guanylyl cyclase GCY-5. Furthermore, GCY-5 activation by the excreted metabolites both suppressed lysosome acidification and promoted lipid translocation in lysosomes via FAT-5/SCD5. This ultimately resulted in the mitigation of radiation-induced damage. The pathway discovered in C. elegans was also confirmed in 293T cells, indicating a potential new target for radiation-induced damage research. A radiotherapy prognosis analysis based on the TCGA database indicated that assessing SCD5 expression in patients with kidney renal clear cell carcinoma (KIRC) during clinical treatment may aid in evaluating their suitability for radiotherapy. This study provides clinicians with a valuable basis for developing more effective therapeutic strategies and an experimental basis for future investigations in this area.