L-Malate Protects Skin Against Ultraviolet-Induced Ferro-Aging

Background: Chronic exposure to ultraviolet (UV) radiation, particularly UVB, is the primary driver of skin photoaging. Ferro-aging, a recently identified iron-triggered, lipid peroxidation-driven cellular senescence program distinct from acute ferroptotic cell death, has emerged as a critical contributor to age-related pathologies, yet its role in skin photoaging remains largely unexplored. Methods: In this study, we systematically evaluated the anti-photoaging efficacy of L-malate (LM), a naturally occurring organic acid, using both in vitro human skin cell models (HaCaT keratinocytes and HSFs) and an in vivo BALB/c nude mouse model of chronic UV irradiation. Results: Our results demonstrate that LM treatment significantly attenuated UVB-induced cellular senescence, DNA damage, and extracellular matrix remodeling in a dose-dependent manner. Mechanistically, LM may act by increasing the expression of malic enzymes (ME1 and ME2), thereby restoring intracellular NADPH levels and glutathione homeostasis. This metabolic restoration effectively blocks the ferro-aging cascade, as evidenced by suppressed ACSL4 upregulation, the maintenance of GPX4 protein levels, and reduced lipid peroxidation. Importantly, topical application of LM in UV-irradiated mice significantly ameliorated in vivo photoaging phenotypes and suppressed ferro-aging markers. Conclusions: In summary, our findings demonstrate that LM may inhibit ferro-aging through the ME1/ME2-NADPH antioxidant axis. This study reveals the possibility of ferro-aging as a potential novel therapeutic target in skin photoaging and suggests that LM is a promising naturally derived ferro-aging inhibitor with translational potential in anti-aging skincare.