Lost in Translation: tRNAs emerge as active regulators in lung disease.

Abstract

The lung is a highly dynamic organ that depends on adaptable protein translation to maintain homeostasis during mechanical, metabolic, and infectious stress. Transcriptomic studies have mapped disease‑associated changes in mRNA expression across diverse lung disorders, but standard RNA‑sequencing approaches largely overlook transfer RNAs (tRNAs), obscuring an important layer of translational control. Recent advances in tRNA‑focused sequencing and functional studies have reframed tRNAs from passive adaptors to active regulators of lung biology. In this mini‑review, we highlight three major regulatory axes of tRNA biology-aminoacyl‑tRNA charging, tRNA methylation, and tRNA‑derived fragments-and their emerging roles in lung injury, infection, and cancer. We discuss how altered tRNA charging in anti-synthetase syndrome and stress response pathways, dysregulated tRNA methylation in lung cancer, and stress‑induced tRNA fragments that signal through pattern‑recognition receptors or Argonaute complexes converge on pathways controlling inflammation, remodeling, and cell survival. Finally, we outline current technical barriers to capturing tRNA species in lung omics and propose opportunities to integrate tRNA biology in future mechanistic and translational research.