Β-Resorcylaldehyde attenuates DSS-induced colitis by inhibiting inflammation and oxidative stress through the Keap1/Nrf2/HO-1 pathway.

BACKGROUND

Ulcerative colitis (UC), a bowel condition marked by heightened oxidative stress, ongoing inflammation, and intestinal barrier dysfunction, has limited therapeutic options that are both effective and safe.

AIM: This study evaluated the therapeutic impacts and mechanisms of β-Resorcylaldehyde (BRAL), the natural phenolic aldehyde derived from Morus alba wood, on dextran sulfate sodium (DSS)-induced UC.

METHODS

A murine DSS-induced UC model was employed to assess the therapeutic effects of BRAL by assessing disease activity, histopathology, oxidative stress, cytokine expression, and intestinal barrier integrity in vivo. To investigate the underlying molecular mechanisms, RNA sequencing, quantitative PCR, and Western blot experiments were conducted. For in vitro validation, RAW264.7 macrophages and THP-1 cells stimulated with lipopolysaccharide and intestinal epithelial cells injured by tert-butyl hydroperoxide were utilized. The assessment of target engagement was carried out using the cellular thermal shift assay, molecular docking, and molecular dynamics simulation.

RESULTS

BRAL markedly alleviated the symptoms of DSS-induced UC, reduced oxidative stress and inflammatory reactions, along with restored tight junction protein expression. Transcriptomic and biochemical analyses indicated that BRAL suppressed pro-inflammatory cytokine production while enhancing antioxidant defenses. Mechanistically, BRAL directly bound to Keap1, thereby promoting Nrf2 nuclear translocation and Nrf2/HO-1 pathway activation. Notably, pharmacological inhibition of Nrf2 with the well-known inhibitor ML385 abolished the protective effects of BRAL.

CONCLUSION

BRAL improves DSS-induced UC through targeting Keap1 to activate Nrf2 signaling, thereby restoring redox homeostasis, suppressing inflammation, and preserving epithelial barrier integrity. These findings suggest that BRAL is a promising natural candidate for treating UC.