14-3-3σ alleviates UVB-induced epidermal oxidative stress through the pentose phosphate pathway promotion.

Ultraviolet B (UVB) radiation, one of the most common environmental pathogenic factors, induces oxidative stress, which is a key mechanism underlying skin damage and the development of various dermatological disorders. The pentose phosphate pathway (PPP) is a major source of NADPH, thereby supporting the cellular antioxidant system and maintaining redox homeostasis. Herein, we established a 14-3-3σ-knockdown HaCaT cell line and combined oxidative stress assessment, RNA-seq, and mass spectrometry-based protein identification to investigate the role and mechanism of 14-3-3σ in regulating redox homeostasis following UVB irradiation. This study revealed that 14-3-3σ knockdown impaired cellular antioxidant capacity and promoted DNA damage accumulation upon UVB irradiation. Mechanistically, 14-3-3σ knockdown promoted the lysosomal degradation of G6PD, the rate-limiting enzyme of the PPP, and reduced YY1-mediated G6PD transcription. Furthermore, restoration of 14-3-3σ expression rescued antioxidant capacity and alleviated DNA damage in UVB-exposed cells, whereas these effects were abolished by pharmacological inhibition of G6PD. Taken together, these findings demonstrated that downregulation of 14-3-3σ suppressed the PPP through G6PD activity inhibition, thereby exacerbating UVB-induced oxidative stress and DNA damage.