Mechanistically, AS-IV was associated with a reduced expression of phosphorylated NF-κB and MAPK proteins, including p-NF-κB, p-IκBα, p-ERK, p-JNK, and p-p38, across the colon, liver, and brain.<h4>Conclusions</h4>AS-IV attenuates DSS-induced multi-organ inflammation via gut-liver-brain axis modulation through NF-κB and MAPK pathway inhibition in experimental colitis models. Here, MAPK8 is linked to colitis.