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Although the secretome (SCT) derived from human umbilical cord mesenchymal stem cells (hUC\u2010MSC 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\u2010exposed mice, restoring epidermal barrier function, dermal collagen integrity, senescence\u2010associated markers, and systemic inflammatory profiles. In UVB\u2010irradiated 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\u2010II flux. By eliminating impaired mitochondria, SCT reduced cytosolic mtDNA leakage, thereby suppressing the overactivation of the cGAS\u2010STING pathway and its downstream pro\u2010inflammatory cytokines IL\u20106, IL\u20108, and IFN\u2010\u03b2. Importantly, these protective effects were abolished by the mitophagy inhibitor Mdivi\u20101, whereas the STING inhibitor H151 effectively reversed the Mdivi\u20101\u2010induced loss of protection, confirming that SCT acts through the hierarchical mitophagy\u2013cGAS\u2010STING axis. Together, our findings establish SCT as a promising cell\u2010free therapeutic strategy for photoaging and highlight the mitophagy\u2013cGAS\u2010STING axis as a critical nexus linking mitochondrial quality control to sterile inflammation in aging tissues.<\/jats:p>","DOI":"10.1111\/acel.70701","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T08:03:22Z","timestamp":1789113802000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Secretome Derived From Human Umbilical Cord Mesenchymal Stem Cells Improves Skin Photoaging by Enhancing Mitophagy to Inhibit the\n                    <scp>cGAS<\/scp>\n                    \u2010\n                    <scp>STING<\/scp>\n                    Pathway"],"prefix":"10.1111","volume":"25","author":[{"given":"Tingting","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Histology and Embryology, School of Basic Medical 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