Hydroxy-α-Sanshool and Capsaicin as Salt Taste Enhancers: Molecular Mechanisms of TRPV1/ENaC Activation and PKCα Signaling

Abstract Excessive salt intake has emerged as a significant public health concern. Early-phase research suggests that pungent substances have the potential to reduce salt consumption, although the precise mechanism remains incompletely elucidated. This study systematically investigated the molecular basis of saltiness enhancement by má là compounds—hydroxy-α-sanshool (3 μmol/L) and capsaicin (1 μmol/L). We employed calcium imaging to monitor ionic flux in murine bud cells, Western blot and qPCR to quantify protein and gene expression in HEK293T cell models, and integrated molecular docking with dynamics simulations to characterize receptor-ligand interactions. Our findings demonstrate that both compounds significantly potentiated Ca²⁺ influx through TRPV1 and SCNN1A channels. Notably, the hydroxy-α-sanshool/capsaicin combination reverses the suppressive effect of capsaicin alone on SCNN1A expression and coordinately upregulates TRPV1 and SCNN1A expression, accompanied by enhanced PKCα phosphorylation. Structural simulations reveal that hydroxy-α-sanshool stabilizes TRPV1 conformational states that facilitate capsaicin binding. Collectively, these results establish a mechanistic foundation for má là–mediated saltiness enhancement and support their potential application in taste modulation strategies.