The Phenolic Signature of Fruits and Leaves Modulates TRPV1 and TRPA1 Transient Receptor Potential Channels: A Metabolomics, In Vitro, and In Silico Study.

Although (strawberry guava, Myrtaceae) is known for its anti-inflammatory, antioxidant, antimicrobial, and antidiabetic properties, its phytochemical profile and associated bioactivities remain largely underexplored. This study employed UHPLC-QTOF-HRMS for untargeted phenolic profiling of leaf and fruit extracts from , followed by semi-quantification of phenolic subclasses and multivariate data analysis. Four hundred sixty-nine metabolites, including various phenolic subclasses-predominantly flavonoids and phenolic acids were- identified and annotated. Using HEK-293 cells stably transfected with TRPA1 or TRPV1 cation channels, it was found that both leaf and fruit extracts activate and rapidly desensitize TRPA1 in a concentration-dependent manner (EC 18 and 30 μg/mL; IC 60 and 47 μg/mL, respectively). Additionally, molecular docking analysis provided deeper insights into the interactions between phytochemicals and the TRPA1 cation channel, identifying theaflavin 3,3'--digallate as the phenolic compound with the highest affinity (S score of -9.27 Kcal/mol). Interestingly, except for theaflavin 3,3'--digallate, compounds enriched in the leaf extract exhibited weaker binding interactions and lower S scores (approximately -7 Kcal/mol) compared to those enriched in the fruit extract. Also, a 100 ns molecular dynamics study of theaflavin 3,3'--digallate with TRAP1 demonstrated high binding stability of the complex. Overall, this study offers valuable insights into the phytochemical characteristics of extracts and reveals their mechanism of action through affinity for the TRPA1 cation channel-receptors.