Alkaline sphingomyelinase (ENPP7) attenuates DSS-induced colitis by modulating FOXO1-mediated antioxidative stress responses

Alkaline sphingomyelinase (alk-SMase), also known as ectonucleotide pyrophosphatase/phosphodiesterase 7 (ENPP7), is an intestinal enzyme involved in sphingolipid metabolism and has been implicated in the regulation of inflammation. However, its role in intestinal inflammation and the underlying mechanisms remain unclear. This study aimed to investigate the role of ENPP7 in dextran sulfate sodium (DSS)-induced colitis, with a particular focus on oxidative stress and FOXO1-related signaling pathways. ENPP7 knockout (KO) and wild-type (WT) mice were used to establish a DSS-induced colitis model. Disease severity was assessed by body weight change, disease activity index (DAI), colon length, histopathological analysis, and plasma oxidative stress markers. Levels of pro-inflammatory cytokines and antioxidant enzymes were measured using standard biochemical assays. In vitro, polarized Caco-2 cells were subjected to ENPP7 knockdown and FOXO1 overexpression to evaluate their roles in antioxidative responses. ENPP7 deficiency significantly aggravated DSS-induced colitis, as evidenced by greater body weight loss, higher DAI scores, and shorter colon length. This effect was accompanied by reduced FOXO1 expression, and was associated with diminished antioxidant defense and mitochondrial dysfunction-related alterations. Additionally, KO mice showed increased levels of pro-inflammatory cytokines (IL-1β and TNF-α) and decreased activities of antioxidant enzymes (CAT and SOD1) in intestinal mucosal tissues compared with WT mice. In Caco-2 cells, ENPP7 knockdown reduced FOXO1 expression, which was associated with impaired antioxidant capacity, whereas FOXO1 overexpression partially reversed these effects. ENPP7 attenuates DSS-induced colitis, at least in part, by modulating FOXO1-mediated antioxidant responses, thereby influencing oxidative stress and inflammatory processes. These findings highlight ENPP7 as a potential therapeutic target for ulcerative colitis, although further mechanistic and clinical studies are warranted.