Background: Capsaicin is an active alkaloid /principal component of red pepper responsible for
the pungency of chili pepper. Capsaicin by changing the intracellular redox homeostasis regulate a variety
of signaling pathways ultimately producing a divergent cellular outcome. Several reports showed the potential
of capsaicin against cancer metastasis, however unexplored molecular mechanism is still an active
part of the research. Several growth factors have a critical role during cancer metastasis among them TGF-
β signaling play a vital role.
Methods: The present study aimed at analyzing capsaicin modulation of TGF-β signaling using network
pharmacology approach. The chemical and protein interaction data of capsaicin was curated and abstracted
using STITCH4.0, PubChem and ChEMBL database. Further, the compiled data set was subjected to the
pathway and functional enrichment analysis using Protein Analysis THrough Evolutionary Relationship
(PANTHER) and, Database for Annotation, Visualization, and Integrated Discovery (DAVID) database.
Meanwhile, the pattern of amino acid composition across the capsaicin targets was analyzed using the EMBOSS
Pepstat tool. Capsaicin targets involved in TGF- β were identified and their Protein-Protein Interaction
(PPI) network constructed using STRING v10 and Cytoscape (v 3.2.1). From the above-constructed network,
the clusters were mined using the MCODE clustering algorithm and finally binding affinity of capsaicin with
its targets involved in TGF-β signaling pathway was analyzed using Autodock Vina.
Results: The analysis explored capsaicin targets and, their associated functional and pathway annotations.
Besides, the analysis also provides a detailed distinct pattern of amino acid composition across the capsaicin
targets. The capsaicin targets described as MAPK14, JUN, SMAD3, MAPK3, MAPK1 and MYC involved
in TGF-β signaling pathway through pathway enrichment analysis. The binding mode analysis of
capsaicin with its targets has shown high affinity with MAPK3, MAPK1, JUN and MYC.
Conclusion: The study explores the potential of capsaicin as a potent modulator of TGF-β signaling pathway
during cancer metastasis and proposes new methodology and mechanism of action of capsaicin
against TGF- β signaling pathway.