# Novel GS5 sericin mitigates UVA-induced photoaging by activating Nrf2 and inhibiting the JAK-STAT pathway

## TL;DR

GS5, a new protein made from silk, helps protect skin from UV damage by activating a protective gene and reducing inflammation.

## Contribution

GS5 is a novel recombinant sericin that combines a PPI inhibitor with anti-photoaging properties through Nrf2 activation and JAK-STAT inhibition.

## Key findings

- GS5 outperformed wild-type sericin and Seq10 in protecting skin cells from UVA damage.
- GS5 reduced senescence markers, ROS, DNA damage, and inflammation in vitro.
- GS5 reversed UVA-induced skin damage in mice and inhibited the JAK-STAT pathway.

## Abstract

Chronic ultraviolet (UV) exposure drives skin degeneration, causing photoaging and increased carcinogenesis risk. To address complex pathogenesis and limited treatments, we developed GS5, a novel anti-photoaging sericin. GS5 fuses natural sericin with Seq10, a Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) protein-protein interaction (PPI) inhibitor identified through molecular docking/dynamics. Seq10 binds Keap1, activates Nrf2 transcription, and alleviates UVA-induced photoaging Nrf2-dependently. Given the application bottlenecks of peptide molecules, we efficiently expressed the GS5 recombinant protein using the silk gland reactor of the silkworm and optimized the enzymatic extraction process to obtain high-activity GS5 sericin. In vitro, GS5 outperformed wild-type (WT) sericin and Seq10, enhancing viability/proliferation in irradiated keratinocytes and fibroblasts while reducing senescence markers (Senescence-associated β-galactosidase (SA-β-gal), P21), reactive oxygen species (ROS), DNA damage, and inflammation. GS5's photoprotection mechanistically requires Nrf2 activation. In vivo, GS5 reversed skin damage in UVA-irradiated mice, improving appearance and histology. RNA-seq implicated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway inhibition via immune/inflammation-related gene modulation. This study innovatively combines a targeted PPI inhibitor with sericin to create GS5, which mitigates photoaging through dual Nrf2 activation and JAK-STAT inhibition, offering a safe, effective, and sustainable therapeutic strategy.