tRNA-derived small RNAs: emerging regulators of ferroptosis in human diseases

tRNA-derived small RNAs (tsRNAs) are functional non-coding RNAs that play crucial roles in transcriptional, translational, and epigenetic regulation. Ferroptosis is an iron-dependent form of programmed cell death driven by lipid peroxidation, and its core mechanisms involve dysregulated iron homeostasis, redox imbalance, and lipid peroxidation. Emerging evidence indicates that tsRNAs serve as pivotal regulators of ferroptosis by targeting key components of the ferroptosis pathway. This regulatory interplay critically influences the activation or suppression of ferroptosis in various human diseases, including non-alcoholic steatohepatitis, perioperative neurocognitive disorders, acute kidney injury, non-small cell lung cancer, gastric cancer, diabetic kidney disease, atrial fibrillation, acute pancreatitis, depression, and acute lung injury, thereby affecting disease pathogenesis, progression, and therapeutic responses. This review summarizes the mechanisms underlying the interplay between tsRNAs and ferroptosis in human diseases and highlights the potential of tsRNAs as novel regulators of ferroptosis, providing insights into disease mechanisms.