Document Type

Article

Publication Title

Systems Level Analysis of Gene, Pathway and Phytochemical Associations with Psoriasis

Abstract

Psoriasis is an inflammatory skin disorder driven by abnormal immune activation that promotes excessive proliferation and accelerated turnover of epidermal keratinocytes. IL-17 and TNF pathways are well known in psoriasis, but the other mechanisms that keep the disease active and link it to systemic comorbidities are not yet fully understood. A combined transcriptomic and systems biology framework was applied to map regulatory circuits in psoriatic lesions and to identify phytochemical candidates capable of multi-target modulation for topical intervention. Differential gene expressions between lesional and healthy skin was analyzed, followed by pathway enrichment, upstream regulator inference, protein-protein interaction network, and chemical-gene interaction mapping. This integrative strategy revealed a transcriptional landscape dominated by type I/III interferon signaling, antiviral and antimicrobial responses, immune metabolic dysregulation, and transcriptional hubs centered on AP-1 and CREB1. Several genes and upstream regulators not previously associated with psoriasis were identified within inflammatory and cell migration-related modules, indicating unexplored regulatory layers in disease control. Network-guided chemical prioritization and direction-of-effect filtering highlighted seven phytochemicals (mahanine, atractylon, protopine, annomontine, taraxasterol, tricin, and tamarixetin) with multi-target activity across key disease axes. ADMET-based screening suggested protopine and atractylon as favorable candidates for topical delivery, while synergy modeling supported flavonoid-alkaloid combination designs. This multi-layered approach provides mechanistically informed phytochemicals targeting the IL-17/TNF-interferon-AP-1/CREB1-COX-2/MMP9 axis in psoriasis. Experimental validation in keratinocyte and organotypic skin models will be required to determine whether these compounds, individually or in combination, can effectively restore psoriatic signaling in vivo.

First Page

1 Introduction Psoriasis is an autoimmune disorder that extends beyond the skin [1]. It affects roughly 2-3% of the population worldwide, and it is more common among Caucasian people than among people living in Asia or Africa [2, 3]. It is associated with several comorbidities, such as inflammatory bowel disease, cardiovascular diseases, metabolic syndrome, and non-alcoholic fatty liver disease [4, 5]. As a result, quality of life for individuals with psoriasis is similar to that of other significant chronic conditions [6]. Epidemiological studies indicate two distinct peaks of disease onset, 20-30 years (early adulthood) and 50-60 years (later adulthood) [3]. Psoriasis develops through an ongoing interaction between inherited susceptibility and environmental factors such as infections, skin injury, psychological stress, and certain medications [7, 8]. At the mechanistic level, the disease develops through a network of interconnected biological processes, where inflammatory molecules released from affected skin can enter the systemic circulation and influence distant organs. This continuous crosstalk among immune cells, skin cells, and connective tissue cells sustains a pathogenic cycle that connects cutaneous inflammation with systemic conditions such as atherosclerosis and insulin resistance [2, 9]. In parallel, at the cellular level, dendritic cells activates Th1 and Th17 lymphocytes and plasmacytoid cells that make type I interferon at the cellular level. These immune cells secrete cytokines, such as (TNF-α), interleukins 17 and 23, interferon-γ, and other mediators, which collectively promote keratinocyte hyperproliferation and perpetuate chronic inflammation [10, 11]. Over the past two decades, therapeutic strategies for moderate to severe psoriasis have shifted from nonspecific immunosuppressive agents to targeted biologic therapies that focus on individual cytokines[12]. Biologic drugs targeting TNF-α, IL-17, or members of IL-23 superfamily have demonstrated dramatic improvements in treatment response, leading to almost complete clearance in patients[7]. However, these drugs are not curative and result in recurrence following discontinuation [13]. Additionally, these drugs are associated with adverse reactions due to severe immune suppression or susceptibility to infections [13]. Most of the current psoriasis treatments act on

Last Page

5 Conclusion This study shows that psoriasis is driven by an interferon-centred, immunometabolic and transcriptional coordinated network rather than a purely cytokine-driven process. Lesional skin displayed strong IL-17/TNF/TLR and HIF-1 signaling alongside metabolic rewiring and a dominant type I/III interferon signature regulated by STAT1, IRF1, IRF3 and IRF7. Network and functional enrichment analyses positioned AP-1 (FOS/JUN) and CREB1 as central regulatory hubs linking inflammatory, metabolic, and matrix-remodeling pathways through key effectors such as IL6, CXCL8, MMP9, FLT1, PPARG and PTGS2. Phytochemical mapping identified seven natural compounds capable of targeting these disease-associated nodes. ADMET profiling highlighted protopine and atractylon as the most suitable candidates for

DOI

doi: https://doi.org/10.64898/2025.12.20.695744

Publication Date

12-22-2025

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