Integrating protein interaction and pathway crosstalk network reveals a promising therapeutic approach for psoriasis through apoptosis induction

• Published in: Scientific reports 2024-09, Vol.14 (1), p.22103-16, Article 22103
• Main Authors: Farahani, Masoumeh, Robati, Reza M., Rezaei-Tavirani, Mostafa, Fateminasab, Fatemeh, Shityakov, Sergey, Rahmati Roodsari, Mohammad, Razzaghi, Zahra, Zamanian Azodi, Mona, Saghari, Saviz
• Format: Article
• Language: English
• Subjects: 631/114; 631/553; 692/699/4033; Acetylcysteine; Acetylcysteine - pharmacology; AKT1 protein; Apoptosis; Apoptosis - drug effects; Arsenic; Arteriosclerosis; Bortezomib; Bortezomib - pharmacology; Curcumin; DNA microarrays; Drug; Gelatinase B; Gene Regulatory Networks; Humanities and Social Sciences; Humans; Interleukin-1beta; Keratinocytes; Keratinocytes - drug effects; Keratinocytes - metabolism; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; multidisciplinary; Pathway crosstalk; Pharmacology; Protein arrays; Protein interaction; Protein Interaction Maps; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Psoriasis; Psoriasis - drug therapy; Psoriasis - metabolism; Psoriasis - pathology; Science; Science (multidisciplinary); Signal Transduction - drug effects; Skin diseases; Stat1 protein; STAT1 Transcription Factor - metabolism; Transcription Factor RelA - metabolism; Transcription factors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-73746-5

Psoriasis is a complex inflammatory skin disease manifested by altered proliferation and differentiation of keratinocytes with dysfunctional apoptosis. This study aimed to identify regulatory factors and comprehend the underlying mechanisms of inefficient apoptosis to open up promising therapeutic approaches. Incorporating human protein interactions, apoptosis proteins, and physical relationships of psoriasis-apoptosis proteins helped us to generate a psoriasis-apoptosis interaction (SAI) network. Subsequently, topological and functional analyses of the SAI network revealed effective proteins, functional modules, hub motifs, dysregulated pathways and transcriptional gene regulatory factors. Network pharmacology, molecular docking and molecular dynamics simulation methods identified the potential drug-target interactions. RELA, MAPK1, MAPK3, MMP9, IL1B, AKT1 and STAT1 were revealed as effective proteins. The MAPK1-MAPK3-RELA motif was identified as a hub regulator in the crosstalk between 41 pathways. Among all pathways, “lipid and atherosclerosis” was found to be the predominant pathway. Acetylcysteine, arsenic-trioxide, β-elemene, bortezomib and curcumin were identified as potential drugs to inhibit pathway crosstalk. Experimental verifications were performed using the literature search, GSE13355 and GSE14905 microarray datasets. Drug-protein-pathway interactions associated with apoptosis were deciphered. These findings highlight the role of hub motif-mediated pathway-pathway crosstalk associated with apoptosis in the complexity of psoriasis and suggest crosstalk inhibition as an effective therapeutic approach.