Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Ganoderic acid D alleviates vascular aging by restoring lysosomal function via stabilization of the VAPB-SNX25 tethering complex.
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Zhang Haiying, Chen Yu, Zhong Zihan, Wang Aiping, Qin Zhenmiao, Piao Shuyan, Huang Xu, Zhang Min, Liu Yan, Liang Jingwei
Аннотация
BACKGROUND: Vascular smooth muscle cell (VSMC) senescence is a major driver of age-related vascular remodeling and functional decline, and is closely associated with lysosomal dysfunction. However, there remains a lack of small molecules capable of precisely targeting lysosomes to improve vascular remodeling.
PURPOSE: This study aimed to identify herbal-derived small molecule that precisely modulate vascular aging systematically and to elucidate its molecular target and mechanisms of action.
METHODS: Utilizing a reverse chemical interference strategy, we matched the transcriptomic signatures of lysosomal dysfunction with herbal pharmacogenomics databases to screen the hit compound. The protective efficacy of it against age-related vascular dysfunction was comprehensively evaluated through histopathology, ultrasonography, and ultrastructural analysis, while the underlying mechanisms of lysosomal membrane repair were elucidated using electron microscopy, immunofluorescence, and computational chemistry.
RESULTS: GA-D was identified and verified to ameliorate vascular senescence and stiffness. GA-D enhanced endoplasmic reticulum (ER)-lysosome colocalization and restored lysosomal acidity in senescent VSMCs. Surface plasmon resonance analysis indicated that GA-D increased the binding affinity between vesicle-associated membrane protein-associated protein B (VAPB) and sorting nexin 25 (SNX25) by approximately fourfold, which is crucial for enhancing ER-lysosome contact. Silencing of VAPB abolished the protective effects of GA-D.
CONCLUSIONS: GA-D mitigates vascular aging by promoting VAPB-dependent lysosomal membrane repair, which improves lysosomal function in VSMCs and subsequently alleviates vascular dysfunction and remodeling. This study thereby proposes both a new target and a lead compound for treating age-related vascular pathologies, successfully demonstrating a reverse chemical perturbation approach.
PURPOSE: This study aimed to identify herbal-derived small molecule that precisely modulate vascular aging systematically and to elucidate its molecular target and mechanisms of action.
METHODS: Utilizing a reverse chemical interference strategy, we matched the transcriptomic signatures of lysosomal dysfunction with herbal pharmacogenomics databases to screen the hit compound. The protective efficacy of it against age-related vascular dysfunction was comprehensively evaluated through histopathology, ultrasonography, and ultrastructural analysis, while the underlying mechanisms of lysosomal membrane repair were elucidated using electron microscopy, immunofluorescence, and computational chemistry.
RESULTS: GA-D was identified and verified to ameliorate vascular senescence and stiffness. GA-D enhanced endoplasmic reticulum (ER)-lysosome colocalization and restored lysosomal acidity in senescent VSMCs. Surface plasmon resonance analysis indicated that GA-D increased the binding affinity between vesicle-associated membrane protein-associated protein B (VAPB) and sorting nexin 25 (SNX25) by approximately fourfold, which is crucial for enhancing ER-lysosome contact. Silencing of VAPB abolished the protective effects of GA-D.
CONCLUSIONS: GA-D mitigates vascular aging by promoting VAPB-dependent lysosomal membrane repair, which improves lysosomal function in VSMCs and subsequently alleviates vascular dysfunction and remodeling. This study thereby proposes both a new target and a lead compound for treating age-related vascular pathologies, successfully demonstrating a reverse chemical perturbation approach.