Dehydroandrographolide Alleviates Oxidative Stress, Inflammatory Response, and Pyroptosis in DSS-Induced Colitis Mice by Modulating Nrf2 Signaling Pathway

Dehydroandrographolide (DA), a bioactive diterpenoid from <i>Andrographis paniculata</i> with diverse biological activity, was investigated for its antioxidant and anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and dextran sulfate sodium (DSS)-induced murine colitis. In vitro, DA inhibited the inflammatory response by modulating extracellular Signal-Regulated Kinase (Erk), c-Jun N-terminal Kinase (Jnk), p38 Mitogen-Activated Protein Kinase (P38), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 activation, and downregulated <i>interleukin-6</i> (<i>il-6</i>) and <i>interleukin-1β</i> (<i>il-1β</i>) mRNA. It also had antioxidant effects by upregulating Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), NAD(P)H quinone dehydrogenase 1 (Nqo-1) and heme oxygenase-1 (Ho-1), promoting protein kinase B (Akt) and 5'-adenosine monophosphate-activated protein kinase-α1 (Ampk-α1) phosphorylation. DA decreased cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNos) levels and alleviated intracellular reactive oxygen species (ROS) accumulation. In vivo, DA alleviated DSS-induced colitis in wild type (WT) mice by improving weight loss, disease activity index, colonic inflammation, and oxidative stress. The beneficial effects were linked to inhibiting Erk, Jnk, and P38 activation and enhancing Nrf2 signaling pathway. DA inhibited NOD-like receptor family pyrin domain-containing 3 (Nlrp3) inflammasome-mediated pryoptosis. However, DA's protective effects were abolished in DSS-induced <i>nrf2</i>^-/- mice, suggesting its efficacy depends on Nrf2 signaling. Overall, DA alleviates oxidative stress, inflammatory responses, and pyroptosis in experimental colitis mice mainly by activating Nrf2 signaling pathway, highlighting its potential as a promising therapeutic option for inflammatory bowel disease.