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.