Sulforaphane Attenuates Ulcerative Colitis by Activating Nrf2 and Suppressing the NLRP3/IL-1β Inflammasome Axis

Ulcerative Colitis (UC) is driven by disrupted epithelial barrier function and chronic inflammation, yet the interaction between oxidative stress and inflammasome signaling remains unclear. This study investigated whether Nrf2 expression correlates with NLRP3 inflammasome activity in intestinal epithelial cells under inflammatory conditions and whether the natural Nrf2 activator, Sulforaphane (SFN), modulates this axis.

A UC-like inflammatory state was established in Caco-2 cells using a cytokine cocktail (TNF-α, LPS, IFN-γ, IL-1β). Nrf2 was silenced using siRNA, and SFN was administered for activate Nrf2. Gene and protein expression were assessed by qPCR, ELISA, and Western blot. Public bulk and single-cell RNA-seq datasets from UC patients were analyzed to validate clinical relevance.

Cytokine stimulation significantly reduced Nrf2 expression while upregulating NLRP3, IL-1β, and IL-18 (p < 0.001). Nrf2 knockdown was associated with enhanced inflammasome activation, as evidenced by increased levels of NLRP3, caspase-1, and pro-inflammatory cytokines. Conversely, SFN pretreatment restored Nrf2 expression and markedly suppressed NLRP3 and IL-18 expression (p < 0.01 to p < 0.001). Multiomic analyses of UC patient samples confirmed an inverse expression pattern between Nrf2 and NLRP3 signaling pathways.

These findings indicate that reduced Nrf2 expression is strongly associated with enhanced NLRP3 inflammasome activation in inflamed intestinal epithelial cells. Pharmacologic activation of Nrf2 by SFN correlates with restored redox balance and attenuated inflammation, supporting the Nrf2-NLRP3 axis as a potential therapeutic target warranting further investigation. Limitations include use of a single cell line and lack of in vivo validation.

This study provides correlative evidence for a redox-inflammasome axis in UC pathogenesis and suggests that further investigation of SFN as a candidate therapeutic approach is warranted.