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

Abstract

Background: Photoaging, a major form of extrinsic skin aging, primarily results from chronic ultraviolet (UV) irradiation. Although accumulating evidence implicates transfer RNA-derived small RNAs (tsRNAs) in aging, inflammation and oxidative stress, their precise roles in photoaging remain insufficiently defined.

Objectives: To investigate the function of tRNA-derived fragment (tRF)-34 in photoaging and to define the underlying molecular mechanism.

Methods: tRF-34 expression was evaluated in UVA1-irradiated primary human dermal fibroblasts (HDFs), murine skin, and sun-exposed human skin using RT-qPCR and fluorescence in situ hybridization. Functional characterization was performed with tRF-34 overexpression and knockdown. Downstream mechanisms were elucidated mainly using RNA sequencing, RNA pull-down, RNA immunoprecipitation and m⁶A methylation analysis.

Results: tRF-34 was significantly downregulated in photoaged HDFs. Restoration of tRF-34 ameliorated photoaging in HDFs, while its inhibition exacerbated senescence-related features. Mechanistically, tRF-34 bound to YTHDF2, inhibiting YTHDF2-mediated m⁶A-dependent degradation of natriuretic peptide receptor C (NPRC) mRNA. NPRC, also diminished in photoaging, exerted photoprotective effects through activation of TGF-β1/Smad signaling. In vivo, tRF-34 overexpression mitigated chronic UVA1-induced wrinkle formation and improved collagen content in photoaged mice.

Conclusions: 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 photoaging.