Suhong Xia

Abnormal intestinal mucosal immunity plays a crucial role in ulcerative colitis (UC). Autotaxin (ATX) can promote T cell migration and was reported to have a regulatory effect on Th17 cells, while sphingosine-1-phosphate (S1P) and its receptors (S1PRs) modulate Th17/Treg balance and inflammation, with S1PR modulators approved for UC. ATX can catalyze sphingosylphosphorylcholine (SPC) to produce S1P; however, the relationship between ATX and S1P/S1PRs in UC is unclear. Understanding the role of ATX-S1P/S1PRs in intestinal immunity can provide new treatment strategies for intestinal inflammatory diseases. Both UC patients and DSS-induced colitic mice showed significantly increased levels of ATX and S1P compared with healthy controls. ATX inhibitor PF8380 treatment led to reduced levels of S1P/S1PRs in colitic mice. Consistent with this, the S1PR antagonist etrasimod was able to alleviate ATX-induced intestinal inflammation, as well as partially restore ATX-induced Th17/Treg imbalance in MLNs and the spleen. In HT-29 and Raw246.7 cells, ATX treatment led to enhanced expression of S1P/S1PRs, with S1PR1 being the most significant. Furthermore, S1PR1 mediates the effect of ATX on Th17/Treg cell differentiation and function in vivo. Therefore, ATX affects the differentiation and function of Th17/Treg cells through S1P/S1PR1 signaling, increased ATX expression leading to Th17/Treg cell imbalance, intestinal mucosal immune dysfunction, and exacerbating intestinal inflammation.

Metabolic dysfunction-associated steatotic liver disease (MASLD), as a metabolic liver disease, is emerging as the most prevalent chronic liver disease worldwide. Metabolic dysfunction-associated steatohepatitis (MASH) is the severe form of MASLD, which progresses from simple steatosis to an inflammatory state, even fibrosis and hepatocellular carcinoma. Accumulating evidence has proved that cell death is a hallmark of MASH, while the specific pathogenesis remains unclear. Several cell deaths, including apoptosis, necroptosis, autophagy, and pyroptosis, have been studied in MASLD/MASH. In recent years, ferroptosis, a novel iron-dependent non-apoptotic form of cell death characterized by the excessive accumulation of intracellular iron and lipid peroxidation, has emerged as a promising target in MASLD/MASH. In this review, we mainly summarize the mechanism of ferroptosis and describe the role of ferroptosis in the progression of MASLD to MASH and related diseases, including liver fibrosis and hepatocellular carcinoma. Then, we discussed the crosstalk between ferroptosis and other cell deaths in MASLD/MASH. Finally, we focus on the potential therapeutic applications of targeting ferroptosis in MASH, which might shed light on the future directions of MASH treatment.