Lanatoside C ameliorates DSS-induced colitis with improved intestinal barrier integrity and reduced M1 macrophage polarization.

Lanatoside C (LanaC), a cardiac glycoside, has been reported to possess therapeutic potential in acute intestinal inflammation; however, its in vivo effects on ulcerative colitis (UC) remain incompletely understood. In this study, we demonstrated that LanaC effectively attenuates DSS-induced colitis in mice by reducing inflammation, mitigating epithelial damage, and preserving barrier integrity. Mechanistically, LanaC treatment was associated with reduced macrophage infiltration in the colon and spleen, suppression of pro-inflammatory M1 macrophage markers, and enhancement of M2-associated markers. In vitro, LanaC inhibited LPS-induced M1 polarization and pro-inflammatory cytokine production in BMDMs, while promoting IL-4-driven M2 polarization and anti-inflammatory cytokine expression. These effects were accompanied by attenuation of STAT1/STAT3 signaling and enhancement of STAT6 activation, suggesting a selective reprogramming of macrophage responses. Collectively, these findings reveal that LanaC alleviates DSS-induced colitis, at least in part, through regulating macrophage infiltration and repolarization supporting its potential as a macrophage-targeted therapeutic candidate in UC.