Superoxide dismutase 3 (SOD3) suppresses periostin to attenuate IL-4/IL-13-driven epithelial inflammation

Superoxide dismutase 3 (SOD3) is an extracellular antioxidant enzyme with an emerging role in the regulation of inflammatory responses; however, its involvement in type 2 cytokine interleukin-4 (IL-4)/interleukin-13 (IL-13)-associated inflammation remains poorly understood. In this study, we investigated the effects of SOD3 on IL-4/IL-13-induced inflammatory responses in human keratinocytes (HaCaT) and bronchial epithelial cells (BEAS-2B). SOD3 significantly suppressed IL-4/IL-13-induced periostin expression at both the mRNA and protein levels in both cell types. Mechanistically, SOD3 interacted with the IL-4 receptor α (IL-4Rα) and attenuated activation of the downstream Janus kinase/signal transducer and activator of transcription 6 (JAK/STAT6) pathway, resulting in reduced periostin expression. Periostin knockdown and recombinant periostin add-back experiments further demonstrated that SOD3 reduced the phosphorylation of nuclear factor-κB (NF-κB), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), largely through suppression of periostin. Consistent with these findings, SOD3 decreased the expression of periostin-associated mediators, including vascular endothelial growth factor (VEGF), thymic stromal lymphopoietin (TSLP), transforming growth factor-β (TGF-β), and matrix metalloproteinases (MMPs), and attenuated periostin-induced production of the pro-inflammatory cytokines tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Collectively, these findings suggest that SOD3 attenuates IL-4/IL-13-driven epithelial inflammation, at least in part, through modulation of the IL-4Rα/JAK/STAT6/periostin axis and downstream NF-κB/MAPK signalling pathways, and suggest its potential as a therapeutic candidate for type 2 inflammatory diseases.

The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05112-3.