Decoding skin aging: Emerging roles of miRNAs, lncRNAs, and circRNAs in mechanisms, therapies, and future horizons.

Abstract

Skin aging is a multifactorial process influenced by intrinsic and extrinsic factors, including cellular senescence, photoaging, glycation, and impaired wound healing, all of which begin at birth. Recent epigenetic research has identified non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), as key regulators of gene networks governing skin homeostasis, regeneration, and aging. However, the literature remains fragmented, lacking a cohesive framework that integrates ncRNA biogenesis, mechanistic function, and therapeutic relevance across aging pathways. This review consolidates current evidence on ncRNA-mediated regulation of skin aging, focusing on their roles in modulating oxidative stress, extracellular matrix remodeling, stem cell exhaustion, and inflammatory signaling. We highlight key ncRNAs such as miR-146a, miR-296-5p, lncRNA-H19, lncRNA-PVT1, and circRNA-406918, and their molecular targets including SIRT1, AQP3, NAMPT, TLR4 and CTSD, coordinating signaling via PI3K/mTOR, AMPK/NAD+ /SIRT, and ERK/p38 MAPK axes. We further address ncRNAs as diagnostic biomarkers and therapeutic candidates in precision dermatology and discuss the translational landscape, including delivery innovations and early-phase clinical studies. While preclinical models show strong promise, clinical applications remain limited, emphasizing the need for human-focused mechanistic and therapeutic research.