Ginsenosides exhibit potential therapeutic potential in photoaging by regulating keratinocyte ferroptosis

Skin photoaging is a chronic inflammatory state induced by ultraviolet (UV) radiation. Ferroptosis has recently emerged as a critical mechanism implicated in the pathogenesis of photoaging. Ginsenosides, active compounds in ginseng, hold potential for treating skin photoaging, but their molecular mechanisms in regulating ferroptosis remain unclear.

We utilized single-cell RNA sequencing (scRNA-seq) to analyze murine skin after UVB irradiation, focusing on keratinocyte subpopulations and ferroptosis-related genes. Molecular docking assessed ginsenoside binding to ferroptosis regulators. Embryotoxicity of ginsenosides was evaluated using zebrafish embryos. Ferroptosis gene expression in UVB-exposed keratinocytes with or without ginsenoside treatment was analyzed by Western blot and RT-qPCR.

scRNA-seq revealed a significant increase in keratinocyte numbers and ferroptosis signals following UVB irradiation. We observed that UVB exposure reduced SLC7A11 and GPX4 expression while increasing HMGB1 in keratinocytes. Molecular docking experiments further indicated that ginsenosides C-K and C-Mc can target ferroptosis-related proteins, and are non-toxic in zebrafish embryos. Treatment with ginsenosides effectively attenuated skin photoaging by modulating the SLC7A11/GPX4 axis and suppressing HMGB1 expression, thereby reducing UVB-induced reactive oxygen species levels and restoring keratinocyte viability. Additionally, we also identified three differentiation trajectories of keratinocytes and found that bone marrow-derived cell Gas6 signaling may influence ferroptosis via the Axl/Tyro3 pathway.

Our findings suggest that ginsenosides may represent promising therapeutic candidates for alleviating UVB-induced skin photoaging via modulation of the ferroptosis-associated SLC7A11/GPX4 axis and HMGB1 expression, providing novel mechanistic insights and therapeutic strategies against skin photoaging.