L-Malate Protects Skin Against Ultraviolet-Induced Ferro-Aging
6 affiliations
- 1Department of Nutrition and Toxicology, School of Public Health and Nursing, Hangzhou Normal University, Hangzhou 311121, China
- 2Department of Neurosurgery and Pharmacy, Hangzhou Third People’s Hospital, Hangzhou 310009, China
- 3Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
- 4Zhejiang Key Laboratory of Cardiovascular Intervention and Precision Medicine, Engineering Research Center for Cardiovascular Innovative Devices of Zhejiang Province, Hangzhou 310016, China
- 5Polytechnic Institute, Zhejiang University, Hangzhou 310015, China
- 6Zhejiang Key Laboratory of Medical Epigenetics, Hangzhou Normal University, Hangzhou 311121, China
Abstract
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.
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BibTeX
@article{xu2026lmalate,
title = {{L-Malate Protects Skin Against Ultraviolet-Induced Ferro-Aging}},
author = {Huanhuan Xu and Chuhui Song and Zhangqi Mao and Wenze Zhang and Hengyu Luo and Xiaoxuan Wu and Yingying Yu and Lili Huang and Liwen Zhang and Zuyong Zhang and Xuexian Fang},
journal = {Metabolites},
year = {2026},
month = oct,
doi = {10.3390/metabo16100775},
url = {https://www.mdpi.com/2218-1989/16/10/775},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - L-Malate Protects Skin Against Ultraviolet-Induced Ferro-Aging
AU - Huanhuan Xu
AU - Chuhui Song
AU - Zhangqi Mao
AU - Wenze Zhang
AU - Hengyu Luo
AU - Xiaoxuan Wu
AU - Yingying Yu
AU - Lili Huang
AU - Liwen Zhang
AU - Zuyong Zhang
AU - Xuexian Fang
PY - 2026
DA - 2026/10/01
JO - Metabolites
DO - 10.3390/metabo16100775
UR - https://www.mdpi.com/2218-1989/16/10/775
AB - 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.
SN - 2218-1989
ER -