Small extracellular vesicles derived from human umbilical cord mesenchymal stem cells attenuate photoaging by modulating the GATA2/PZP/GRP75 axis

The skin is one of the earliest organs in the human body to exhibit signs of aging, with photoaging mainly caused by chronic ultraviolet (UV) exposure and recognized as a major form of extrinsic aging. Small extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hucMSC-sEVs) have been shown to delay skin aging by upregulating pregnancy zone protein (PZP), which modulates inflammatory responses, oxidative stress, and extracellular matrix remodeling. However, the core regulatory network underlying these effects remains unclear. Focusing on PZP, this study integrated bioinformatics to identify GATA2 as a potential upstream transcriptional regulator and GRP75 as a possible downstream target, indicating a GATA2/PZP/GRP75 signaling axis that may regulate photoaging. ChIP assays and dual-luciferase reporter analyses confirmed that GATA2 binds to the promoter region of PZP and upregulates its transcription. Knockdown and overexpression experiments further demonstrated that GATA2 suppresses or promotes PZP expression, thereby significantly influencing the senescence phenotype of dermal fibroblasts under UV irradiation. In addition, protein docking, co-immunoprecipitation (CoIP), and immunofluorescence colocalization assays validated the interaction between PZP and GRP75. PZP alleviates mitochondrial calcium overload and dysfunction by inhibiting the abnormal elevation of GRP75, thus delaying photoaging. These findings offer novel insights and targets for skin-aging intervention.