The Secretome Derived From Human Umbilical Cord Mesenchymal Stem Cells Improves Skin Photoaging by Enhancing Mitophagy to Inhibit the cGAS-STING Pathway.

Abstract

Ultraviolet (UV)-induced skin photoaging is driven by cellular senescence and chronic inflammation. Although the secretome (SCT) derived from human umbilical cord mesenchymal stem cells (hUC-MSC SCT) exhibits regenerative potential, its role in combating photoaging remains to be elucidated. In this study, we show that SCT markedly ameliorates photoaging in UV-exposed mice, restoring epidermal barrier function, dermal collagen integrity, senescence-associated markers, and systemic inflammatory profiles. In UVB-irradiated human immortalized keratinocytes (HaCaT), SCT enhanced cellular viability, proliferation, and migration while alleviating cellular senescence. Mechanistically, SCT promoted mitophagy, as indicated by clearance of mitochondrial proteins (TOM20, TIM23, HSP60), reversal of p62 accumulation, and restoration of LC3B-II flux. By eliminating impaired mitochondria, SCT reduced cytosolic mtDNA leakage, thereby suppressing the overactivation of the cGAS-STING pathway and its downstream pro-inflammatory cytokines IL-6, IL-8, and IFN-β. Importantly, these protective effects were abolished by the mitophagy inhibitor Mdivi-1, whereas the STING inhibitor H151 effectively reversed the Mdivi-1-induced loss of protection, confirming that SCT acts through the hierarchical mitophagy-cGAS-STING axis. Together, our findings establish SCT as a promising cell-free therapeutic strategy for photoaging and highlight the mitophagy-cGAS-STING axis as a critical nexus linking mitochondrial quality control to sterile inflammation in aging tissues.