Uncovering a Hub Signaling Pathway of Antimicrobial-Antifungal-Anticancer Peptides' Axis on Short Cationic Peptides via Network Pharmacology Study.

Short cationic peptides (SCPs) with therapeutic efficacy of antimicrobial peptides (AMPs), antifungal peptides (AFPs), and anticancer peptides (ACPs) are known as an enhancement of the host defense system. Here, we investigated the uppermost peptide(s), hub signaling pathway(s), and their associated target(s) through network pharmacology. Firstly, we selected SCPs with positive amino acid residues on N- and C- terminals under 500 Dalton via RStudio. Secondly, the overlapping targets between the bacteria-responsive targets (TTD and OMIM) and AMPs' targets were visualized by VENNY 2.1. Thirdly, the overlapping targets between AFPs' targets and fungal-responsive targets were exhibited by VENNY 2.1. Fourthly, the overlapping targets between cancer-related targets (TTD and OMIM) and fungal-responsive targets were displayed by VENNY 2.1. Finally, a molecular docking study (MDS) was carried out to discover the most potent peptides on a hub signaling pathway. A total of 1833 SCPs were identified, and AMPs', AFPs', and ACPs' filtration suggested that 197 peptides (30 targets), 81 peptides (6 targets), and 59 peptides (4 targets) were connected, respectively. The AMPs-AFPs-ACPs' axis indicated that 27 peptides (2 targets) were associated. Each hub signaling pathway for the enhancement of the host defense system was "Inactivation of Rap1 signaling pathway on AMPs", "Activation of Notch signaling pathway on AMPs-AFPs' axis", and "Inactivation of HIF-1 signaling pathway on AMPs-AFPs-ACPs' axis". The most potent peptides were assessed via MDS; finally, HPIK on STAT3 and HVTK on NOS2 and on HIF-1 signaling pathway were the most stable complexes. Furthermore, the two peptides had better affinity scores than standard inhibitors (Stattic, 1400 W). Overall, the most potent SCPs for the human defense system were HPIK on STAT3 and HVTK on NOS2, which might inactivate the HIF-1 signaling pathway.