Targeting ferroptosis in photoaging: mechanisms and therapeutic potential of adipose-derived stem cell exosomes

Skin photoaging is a form of premature cutaneous aging caused by chronic ultraviolet (UV) exposure, manifesting as wrinkling, laxity, and pigmentary disturbances. UV radiation generates reactive oxygen species and upregulates matrix metalloproteinases, leading to extracellular matrix degradation. Emerging evidence implicates ferroptosis - an iron-dependent form of regulated cell death characterized by lipid peroxidation - in ultraviolet B (UVB)-induced photodamage. Studies show that glutathione peroxidase 4 (GPX4)-dependent antioxidant defenses are compromised in UV-exposed skin cells, and ferroptosis inhibitors can partially attenuate UV-induced cellular damage. Exosomes derived from adipose-derived stem cells (ADSC-Exos) have emerged as a promising cell-free regenerative strategy for skin rejuvenation. These 30-150 nm extracellular vesicles offer advantages over whole-cell therapy, including low immunogenicity, reduced tumorigenic concerns compared with replicating cells, and easier standardization. Through paracrine signaling, ADSC-Exos deliver bioactive proteins and non-coding RNAs that promote collagen synthesis, angiogenesis, and anti-inflammatory effects. Circular RNAs (circRNAs) are highly enriched and stable in exosomes due to their covalently closed structure. Notably, hypoxic-preconditioned ADSC-Exos deliver circ-Ash1l into UVB-damaged skin cells, where it sequesters miR-700-5p and upregulates GPX4. This circ-Ash1l/miR-700-5p/GPX4 axis inhibits ferroptotic cell death, reduces oxidative damage, and attenuates UVB-induced photoaging phenotypes in vitro and in vivo. This review summarizes the mechanisms of UVB-mediated photoaging and ferroptosis, the therapeutic potential of adipose-derived stem cell-derived exosomes, the role of exosomal circRNAs, and engineering strategies to enhance exosome therapy. We also discuss clinical translation challenges, including manufacturing, quality control, and regulatory considerations.