A tRNA-derived RNA fragment protects skin from photoageing by preserving collagen and mRNA stability.

Abstract

Photoageing, a major form of extrinsic skin ageing, primarily results from chronic ultraviolet (UV) irradiation. Although accumulating evidence implicates tRNA-derived small RNAs (tsRNAs) in ageing, inflammation and oxidative stress, their precise roles in photoageing remain insufficiently defined. To investigate the function of tRNA-derived fragment (tRF)-34 in photoageing and to define the underlying molecular mechanism. tRF-34 expression was evaluated in UVA1-irradiated primary human dermal fibroblasts (HDFs), murine skin and sun-exposed human skin, using reverse transcription quantitative polymerase chain reaction and fluorescence in situ hybridization. Functional characterization was performed with tRF-34 overexpression and knockdown. Downstream mechanisms were elucidated mainly using RNA sequencing, RNA pulldown, RNA immunoprecipitation and m⁶A methylation analysis. tRF-34 was significantly downregulated in photoaged HDFs. Restoration of tRF-34 ameliorated photoageing in HDFs, while its inhibition exacerbated senescence-related features. Mechanistically, tRF-34 bound to YTH domain family protein 2 (YTHDF2), inhibiting YTHDF2-mediated m⁶A-dependent degradation of NPR3 mRNA. Natriuretic peptide receptor C (NPRC), also diminished in photoageing, exerted photoprotective effects through activation of transforming growth factor-β1/SMAD signalling. In vivo, tRF-34 overexpression mitigated chronic UVA1-induced wrinkle formation and improved collagen content in photoaged mice. Our work establishes a novel tRF-34/YTHDF2/NPRC regulatory axis that preserves skin homeostasis against chronic UV damage, providing new mechanistic insights and suggesting a potential basis for future translational exploration in photoageing.