Ganoderic acid D alleviates vascular aging by restoring lysosomal function via stabilization of the VAPB–SNX25 tethering complex

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.