Targeting Endothelial KDM5A to Attenuate Aging and Ameliorate Age‐Associated Metabolic Abnormalities

This study identifies endothelial KDM5A as a key regulator of aging. KDM5A deficiency accelerates aging by enhancing H3K4me3‐mediated FABP4 expression, disrupting fatty acid metabolism, and promoting multi‐organ senescence. KDM5A restoration or FABP4 inhibition reverses these adverse effects and extends lifespan, positioning the KDM5A/FABP4 axis as a potential therapeutic target for vascular aging and metabolic disorders. Abstract Vascular aging accelerates the gradual deterioration of systemic organ function, yet its key driving factors are still largely unexplored. Here, it is demonstrated that lysine‐specific demethylase 5A (KDM5A) decreases and histone H3 lysine 4 (H3K4me3) increases in vascular endothelial cells (VECs) isolated from ageing mice and VEC senescence models. KDM5A deficiency exacerbated endothelial cell aging in vitro. Endothelial‐specific KDM5A‐deficient mice exhibit shortened lifespan and multiple senescent phenotypes, including fat accumulation, reduced thermogenic capacity, skeletal kyphosis, and age‐related liver lesions, while maintaining VECs‐specific KDM5A levels attenuates these adverse metabolic abnormalities and prolongs lifespan. Mechanistically, endothelial KDM5A deficiency aggravates aging‐associated fatty acid (FA) metabolism disorders by enhancing H3K4me3 enrichment at the promoter region of FA‐binding protein 4 (FABP4), which leads to active FABP4 transcription. Together, the study reveals the regulatory mechanisms of KDM5A in age‐dependent metabolic disorders and identifies KDM5A/FABP4 axis as a potential therapeutic target for vascular aging and related organ dysfunction. This study identifies endothelial KDM5A as a key regulator of aging. KDM5A deficiency accelerates aging by enhancing H3K4me3-mediated FABP4 expression, disrupting fatty acid metabolism, and promoting multi-organ senescence. KDM5A restoration or FABP4 inhibition reverses these adverse effects and extends lifespan, positioning the KDM5A/FABP4 axis as a potential therapeutic target for vascular aging and metabolic disorders. Abstract Vascular aging accelerates the gradual deterioration of systemic organ function, yet its key driving factors are still largely unexplored. Here, it is demonstrated that lysine-specific demethylase 5A (KDM5A) decreases and histone H3 lysine 4 (H3K4me3) increases in vascular endothelial cells (VECs) isolated from ageing mice and VEC senescence models. KDM5A deficiency exacerbated endothelial cell aging in vitro. Endothelial-specific KDM5A-deficient mice exhibit shortened lifespan and multiple senescent phenotypes, including fat accumulation, reduced thermogenic capacity, skeletal kyphosis, and age-related liver lesions, while maintaining VECs-specific KDM5A levels attenuates these adverse metabolic abnormalities and prolongs lifespan. Mechanistically, endothelial KDM5A deficiency aggravates aging-associated fatty acid (FA) metabolism disorders by enhancing H3K4me3 enrichment at the promoter region of FA-binding protein 4 ( FABP4 ), which leads to active FABP4 transcription. Together, the study reveals the regulatory mechanisms of KDM5A in age-dependent metabolic disorders and identifies KDM5A/FABP4 axis as a potential therapeutic target for vascular aging and related organ dysfunction. Advanced Science, EarlyView.