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Ganoderic acid D alleviates vascular aging by restoring lysosomal function via stabilization of the VAPB-SNX25 tethering complex
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DOI：10.1016/j.phymed.2026.158153.png)
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Abstract
En 中文
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.
Keywords:
GA-D
Vascular aging
VSMCs
Lysosome
VAPB
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