RNA on the menu: tRNA-derived small RNAs as novel autophagy regulators in renal homeostasis

Transfer RNA-derived small RNAs (tDRs) have transcended their traditional roles in protein synthesis and have emerged as crucial regulators of cellular homeostasis. Li et al. (2025) underscored this by identifying tRNA-Asp-GTC-3'tDR as a tDR responsive to hypoxic conditions, which confers renal protection through a distinctive macroautophagy/autophagy mechanism. This tDR adopts a G-quadruplex structure that sequesters PUS7 (pseudouridine synthase 7), thereby disrupting the pseudouridylation of histone mRNAs and directing them toward degradation via autophagosome-lysosome pathways, a mechanism termed "RNautophagy." Clinically, elevated levels of tRNA-Asp-GTC-3'tDR in conditions such as preeclampsia and early chronic kidney disease suggest a conserved evolutionary pathway for renal protection in humans. Experimental studies in mice have demonstrated that therapeutic enhancement of tDR mitigates renal inflammation, fibrosis, and damage, whereas its inhibition exacerbates these conditions. This establishes a novel paradigm linking RNA biology and autophagy regulation, paving the way for innovative precision RNA-based therapies for kidney diseases.Abbreviations: mRNAs: messenger RNA; PUS7: pseudouridine synthase 7; tDRs: transfer RNA-derived small RNAs; tRNA-Asp-GTC-3'tDR: transferRNA-aspartic acid-GTC-codon-3'terminal deoxyribonucleotide.