ADSCs-Exo ameliorates UVB-induced skin DNA damage via p62-RNF168-dependent histone ubiquitination

Mesenchymal stem cell-secreted paracrine factors, especially exosome, has emerged as promising therapeutic candidates for mitigating UVB-induced cutaneous photodamage. While adipose-derived stem cell exosome (ADSCs-Exo) are well documented to alleviate UVB-triggered DNA damage, the precise molecular mechanisms underlying this effect remain poorly elucidated. Herein, we illustrated that ADSCs-Exo drastically curbed UVB-elicited cellular apoptosis, cell cycle arrest, comet tail formation, γH2AX foci accumulation, and cyclobutane pyrimidine dimer deposition in HaCaT keratinocytes. Consistent with the in vitro findings, ADSCs-Exo substantially mitigated cutaneous DNA damage and skin cell apoptosis in UVB-exposed Kunming mice. Notably, pharmacological autophagy blockade using 3-methyladenine effectively abolished these ADSCs-Exo-dependent protective outcomes. Mechanistically, ADSCs-Exo treatment facilitated the degradation of core autophagy receptors, including p62, NBR1, and TAX1BP1. Subsequent functional validation assays identified ectopic p62 overexpression as the sole manipulation capable of counteracting ADSCs-Exo's cytoprotective potency. Co-immunoprecipitation assays further verified a direct interaction between p62 and the E3 ubiquitin ligase RNF168. P62 overexpression hindered RNF168 recruitment to DNA lesion sites, accompanied by suppressed histone K63-linked polyubiquitination and H2AX ubiquitination, as well as impaired recruitment of the DNA damage repair factors BRCA1 and RAD51. Furthermore, genetic knockdown of RNF168 markedly diminished histone H2AX ubiquitination and compromised the protective functions of ADSCs-Exo. Collectively, this study uncovered a novel autophagy-dependent p62-RNF168 regulatory axis governing ADSCs-Exo-mediated photoprotection, providing a promising therapeutic strategy for ultraviolet-associated skin DNA damage and photocarcinogenesis.