LncRNA NONMMUT051252 promotes atopic dermatitis via the miR-141-5p/USP14/cGAS-STING axis and ferroptosis

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by epidermal barrier dysfunction and persistent pruritus. However, the molecular mechanisms linking non-coding RNA regulation to ferroptosis and inflammatory signaling in AD remain poorly understood.

A 2,4-dinitrochlorobenzene (DNCB)-induced mouse model of AD and a TNF-α + IFN-γ-induced inflammatory keratinocyte model were established. Gain- and loss-of-function experiments were performed using transfection approaches. Molecular interactions were validated by dual-luciferase reporter, co-immunoprecipitation, and deubiquitination assays. Inflammatory responses and ferroptosis were evaluated by Western blotting, ELISA, and biochemical analyses.

The lncRNA 051252/miR-141-5p/USP14 regulatory axis was significantly dysregulated in AD-like skin lesions and inflammatory keratinocytes. Silencing lncRNA 051252 or overexpressing miR-141-5p markedly attenuated inflammatory responses and ferroptosis both in vivo and in vitro. Mechanistically, lncRNA 051252 functioned as a competing endogenous RNA by sponging miR-141-5p, thereby relieving its inhibitory effect on USP14. miR-141-5p directly targeted USP14, whereas USP14 stabilized cGAS by removing K48-linked ubiquitin chains, resulting in activation of the STING signaling pathway and promotion of ferroptosis. Furthermore, pharmacological inhibition of cGAS-STING signaling recapitulated the protective effects of lncRNA 051252 silencing and miR-141-5p overexpression.

These findings identify a previously unrecognized lncRNA 051252/miR-141-5p/USP14/cGAS-STING signaling axis that drives inflammatory responses and ferroptosis in AD, providing new mechanistic insights into disease pathogenesis and highlighting potential therapeutic targets.