Exploring the Interplay of PI3K/AKT/mTOR and JNK Signaling Pathways in Psoriasis: Insights from Systematic Review and Network Pharmacology Approach

Introduction: Psoriasis is a chronic inflammatory skin disease characterized by excessive keratinocyte proliferation, abnormal differentiation, and infiltration of inflammatory cells. Central to its pathogenesis are the PI3K/AKT/mTOR and JNK signaling pathways, which regulate inflammation and keratinocyte behavior. Methods: This study reviewed experimental data reported in the scientific literature and utilized network pharmacology to investigate the interplay between the PI3K/AKT/mTOR and JNK pathways, aiming to elucidate the underlying mechanisms of psoriasis. 709 records from Scopus, Web of Sciences, Cochrane Library and PubMed were reviewed without limitations until October 3, 2023. 85 articles were included in the systematic review. Results: Key molecules, including EGFR, Sortilin, and Cyr61, were identified as important links between these pathways, influencing cell survival and apoptosis. Flavonoids such as Rhododendrin, Erianin, and Fisetin were found to effectively target both of these pathways, potentially modifying cellular behavior and offering therapeutic benefits. The network analysis revealed that EGFR and AKT serve as critical connectors between hub genes CDC42 and GAPDH, with these flavonoids impacting downstream signaling molecules, including PI3K, AKT, mTOR, Grb2, JAK, STAT, Cyclooxygenase, HIF-1α, and MAPKs. Discussion: The findings highlight the pivotal role of the PI3K/AKT/mTOR pathway in promoting inflammation and cellular proliferation by activating NF-κB and HIF-1α. Conclusion: This comprehensive review underscores the importance of the PI3K/AKT/mTOR and JNK pathways in understanding psoriasis mechanisms. Targeting these pathways with flavonoids may offer promising therapeutic strategies by modulating key molecular hubs involved in disease progression.