Stress granule assembly drives an adaptive survival response in keratinocytes under TiO2 nanoparticles and UV irradiation

Nanoscale processing enhances the photocatalytic reactivity of titanium dioxide nanoparticles (TiO 2 NPs) under UV exposure. While these nanoparticles are widely utilized in cosmetics and industrial formulations, the molecular decision-making processes that dictate keratinocyte survival following UV exposure remain poorly understood. Here, we demonstrate that concurrent exposure to TiO 2 NPs and UVA radiation induces substantial synergistic phototoxicity, which does not occur under individual exposure at the same respective doses. Under phototoxic conditions, keratinocytes were found to engage an adaptive response characterized by G3BP1-dependent stress granule (SG) assembly to mitigate cellular stress. Mechanistically, this cytoprotective response was driven by PERK/eIF2α signaling and coordinated by endoplasmic reticulum–mediated calcium flux. Pharmacological inhibition of SG assembly or genetic knockdown of G3BP1 exacerbated cell death, indicating that SG formation serves as a cytoprotective mechanism that relieves proteotoxic burden. Collectively, these findings delineate a proteostatic defense mechanism against TiO 2 -mediated phototoxicity, providing fundamental insights for the safe-by-design evaluation of advanced dermatological materials.