Integrated systems toxicology identifies TCDD-responsive targets linked to immune dysregulation and treatment response in psoriasis.

BACKGROUND

Psoriasis is a chronic immune-mediated inflammatory skin disease driven by dysregulation of the IL-23/IL-17 axis and influenced by genetic and environmental factors. The role and molecular mechanisms of the environmental pollutant dibenzo-p-dioxins, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in psoriasis remain unclear.

METHODS

An integrative strategy combining network toxicology, machine learning, bioinformatics analysis, molecular simulation, and in vitro keratinocyte qRT-PCR validation was employed to systematically investigate the potential toxicity and molecular mechanisms of TCDD in psoriasis.

RESULTS

Eighty-seven overlapping genes were identified between TCDD-related targets and psoriasis-associated genes and were mainly enriched in IL- 17-, chemokine-, MAPK/ ERK-, and GPCR-related signaling pathways. Machine learning identified five core target genes-LCK, MMP9, CXCR2, PTAFR, and CCNB1-which were significantly upregulated in psoriatic lesions, showed strong diagnostic performance within the analyzed datasets, and were associated with local immune infiltration patterns. Structural analyses supported potential interactions between TCDD and these core targets, with CXCR2 showing the most favorable predicted docking score. A 24-h keratinocyte TCDD-response signature showed significant concordance with psoriatic lesional transcriptomes, and keratinocyte qRT-PCR validation showed increased expression of LCK, MMP9, CXCR2, and PTAFR, whereas CCNB1 showed only a modest change. In biologic-therapy cohorts, core genes were downregulated after 12 weeks, and higher baseline MMP9 was associated with poorer clinical improvement and may have potential relevance to treatment response.

CONCLUSION

Our integrative analyses identify TCDD-associated genes and pathways potentially involved in psoriasis immune dysregulation. Structural modeling supports the in silico plausibility of TCDD engaging CXCR2, while transcriptomic concordance and keratinocyte qRT-PCR findings support dysregulation of several core genes in epidermal cells. Baseline MMP9 was associated with week-12 treatment response in biologic-therapy cohorts. Nevertheless, the link between environmental TCDD exposure and psoriasis remains inferential because the study relied mainly on in silico analyses without individual-level exposure data; therefore, further validation in well-designed cohort studies is needed.