Mechanistic insights into sitagliptin-induced skin autoimmunity: Linking environmental drug exposure to IL-6 activation in bullous pemphigoid.

BACKGROUND

Pharmaceutical residues, particularly antidiabetic agents such as sitagliptin, have become emerging environmental pollutants due to their incomplete removal during wastewater treatment and high persistence in aquatic systems. Increasing detection of sitagliptin in sewage and surface water raises concerns about its potential ecological and human health effects. Recent clinical observations suggest that DPP4 inhibitors may be linked to bullous pemphigoid (BP), an autoimmune blistering skin disease, but the underlying mechanisms remain unclear.

OBJECTIVES

This study aimed to elucidate the molecular mechanisms by which environmental exposure to sitagliptin may induce skin toxicity and contribute to the onset of BP.

METHODS

An integrative strategy combining computational toxicology and experimental validation was employed. Toxicity prediction using ADMETlab 3.0 indicated potential cutaneous toxicity of sitagliptin. Network toxicology and enrichment analyses identified ten candidate targets mainly involved in inflammatory and immune pathways. HaCaT cell assays, immunohistochemistry, ELISA, and transcriptomic profiling were performed to validate computational predictions.

RESULTS

Sitagliptin exposure significantly upregulated IL-6 expression in keratinocytes, consistent with the elevated IL-6 levels observed in BP patient tissues and sera. Pathway analyses indicated that sitagliptin perturbs IL-17 and cytokine signaling pathways and promotes immune activation, implicating IL-6 as a central mediator of its pro-inflammatory effects.

CONCLUSIONS

This study provides the first mechanistic evidence linking sitagliptin exposure to BP via IL-6-mediated immune dysregulation. Our findings highlight the potential dermatotoxic and immunotoxic risks of pharmaceutical contaminants in the environment and underscore the importance of integrating network toxicology with experimental approaches for environmental health risk assessment.