NRF2-mediated autophagic degradation of glycated vimentin in the skin by an elastin-derived peptide.

BACKGROUND: Advanced glycation end products (AGEs) contribute significantly to skin ageing by inducing cross-linking of dermal proteins and promoting oxidative stress. Vimentin, a long-lived intermediate filament protein, is particularly susceptible to glycation and serves as a biomarker for skin ageing and fibrosis. NRF2 (nuclear factor erythroid 2-related factor 2) is a key regulator of cellular defense mechanisms, including antioxidant responses and autophagy. METHODS: We evaluated the anti-glycation and pro-regenerative properties of a trifunctional elastin-derived peptide (TFP) in human dermal fibroblasts (in vitro), skin explants (ex vivo), and in a clinical cosmetic study (in vivo). Vimentin glycation and expression were assessed alongside NRF2 pathway activation. Transcriptomic analysis (RNA-seq) in fibroblasts under glyoxal-induced stress identified TFP-regulated genes, further validated by RT-qPCR in skin explants. RESULTS: TFP reduced vimentin glycation across all models. In skin explants, total vimentin levels decreased without changes in VIM mRNA expression, suggesting enhanced degradation rather than transcriptional repression. TFP activated the NRF2 pathway, leading to modulation of genes involved in protein homeostasis, including autophagy, proteasomal degradation and anti-inflammatory regulation. Clinical results supported the anti-wrinkle and anti-ageing effects of TFP. CONCLUSION: TFP activates NRF2-mediated detoxification and protein clearance pathways, facilitating the removal of glycated vimentin. These results highlight TFP's anti-ageing, anti-fibrotic, and anti-inflammatory potential, positioning it as a promising therapeutic candidate for ageing-related skin conditions and disorders associated with proteostasis imbalance.