Involvement of Ferroptosis in Bullous Pemphigoid Pathogenesis

ABSTRACT Background Bullous pemphigoid (BP) primarily affects the elderly and frequently coexists with ferroptosis‐related conditions, such as cardiovascular and immune‐mediated diseases. However, little is known about how ferroptosis affects BP formation. Here, we investigate the role of ferroptosis in the pathogenesis of BP and its impact on disease prognosis. Methods Single‐cell and bulk RNA‐seq were used to analyze ferroptosis driver gene expression in BP patients. We used quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR), immunofluorescence, and western blot assay to analyze ferroptosis relevant mRNA and proteins in the skin lesions. Western blot assay, flow cytometer, and iron assay were used to confirm ferroptosis involvement in BP blister fluid stimulated HaCaT cells. Enzyme‐linked immunosorbent assay (ELISA) detection of ferroptosis related blood biomarkers to evaluate the disease prognosis. Results ScRNA‐seq data of BP lesions showed abnormal trends in ferroptosis‐related genes GPX4, VDAC2, VDAC3. The decreased mRNA expression of GPX4, XCT, and FTH1, while increased levels of VDAC2, VDAC3 and TRFC were found in BP lesions. The similar results were observed in HaCaTs treated with blister fluid from BP patients. Additionally, BP serum levels of ferritin, transferrin, and ferroptosis‐related cytokines high mobility group box 1 (HMGB1), interleukin (IL)‐5, IL‐6, IL‐18, IL‐31, and IL‐1β were elevated, which decreased following successful treatment. In vitro, blister fluid promoted the production of above cytokines, enhanced total iron, Fe 2+ , and reactive oxygen species (ROS) levels. Moreover, serum ferritin levels showed significant correlation with the Bullous Pemphigoid Disease Area Index (BPDAI), anti‐180 antibody, and C‐reactive protein (CRP) levels. Conclusions Ferroptosis plays an important role in the pathophysiology of BP and may predict disease prognosis. Interventions targeting ferroptosis could be beneficial for the treatment of BP.