Majoon Ushba alleviated IL-17A sensitized keratinocyte ferroptosis via JAK-2-STAT-3 signaling axis and reversed imiquimod induced psoriasiform inflammation.

Abstract

CONTEXT: Psoriasis is a relapsing autoimmune disease exacerbated by aberrant interleukin (IL)-17 A activity. Majoon Ushba, a unani polyherbal formulation implicated in clinical cases of psoriasis lacks immunopharmacological validation. OBJECTIVE: The study aims to investigate the pre-clinical efficacy of Majoon Ushba and its therapeutic role in mitigating IL-17A-induced keratinocytes ferroptosisablation of JAK-2/STAT-3 pathway. MATERIALS AND METHODS: HaCaT cells were stimulated with IL-17A to assess the activation of the JAK-2-STAT-3 pathway. The STAT-3 inhibitor, S3I-201, was used to confirm the role of the STAT-3 axis in keratinocyte ferroptosis. Majoon Ushba pretreatment was assessed to determine its efficacy in alleviating keratinocyte ferroptosis. An imiquimod (IMQ)-induced psoriasis mouse model was used to evaluate the pre-clinical efficacy of Majoon Ushba. Furthermore, prior high-performance liquid chromatography (HPLC) profiling was leveraged for in-silico docking analysis to identify the binding affinities of key phytoconstituents with IL-17RA and STAT-3. RESULTS: Majoon Ushba alleviated the IL-17A/JAK-2-STAT-3 axis, improved GPX4 expression, and regulated lipid peroxidation. Subsequently, Majoon Ushba also reversed the expression of pathogenic mediators and led to a reduction in serum cytokine levels of IL-17A, IL-23, and IFN-γ. An in-silico docking analysis suggested favorable binding affinities for key phytoconstituents of Majoon Ushba against IL-17RA and STAT-3. Aligned with pre-clinical andresults, the computational findings offer initial evidence that the polyherbal formulation may influence the IL-17A/JAK-2-STAT-3 signaling pathway. DISCUSSION AND CONCLUSION: In conclusion, our preliminary findings reveal a plausible mechanistic basis for the anti-psoriatic efficacy of Majoon Ushba, warranting larger clinical trials in psoriasis patient cohorts.