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.

Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer and has an increasing incidence worldwide. The management of HCC still has many restrictions, despite the fact that there are now numerous treatment options, including liver transplantation/resection, locoregional treatments (LRT), and systemic medication. As a turning point in the history of cancer treatment, the discovery of the immune checkpoints and the development of their inhibitors provide new hope for HCC patients. However, limited objective response rate and insignificant overall survival improvement are still urgent problems to be solved for immune checkpoint inhibitors (ICIs). Combination therapies are considered a solution for improving the effectiveness and response rate of ICIs, and several forms of combination treatments are currently being actively researched. In this review, we summarize the mainstream combination strategies, explain their theoretical basis, introduce several important and ongoing clinical trials, and suggest some potential future paths in this area at the conclusion of the review. AVAILABILITY OF DATA AND MATERIALS: Not applicable.

Metabolic dysfunction-associated steatohepatitis (MASH) represents an advanced stage of fatty liver disease characterized by hepatocyte ballooning, cell death, inflammation and fibrosis. Fatty acid transport protein 5 (FATP5), a hepatocyte-specific transmembrane protein, mediates both long-chain fatty acids (LCFAs) uptake and bile acids (BAs)-coenzyme A (CoA) conjugation. While FATP5 upregulation has been documented in MASH patients, its functional role in disease progression through hepatic lipid metabolic regulation remains unclear. In this study, we identified FATP5 elevation both in vitro and in vivo MASH models. Treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) significantly attenuated MASH histopathology and steatotic HepG2 cell death. Furthermore, FATP5 deficiency protected against methionine-choline-deficient diet (MCD)-induced MASH in the mouse model and prevented steatotic HepG2 cell deaths through reducing ferroptosis. Notably, we discovered an inverse correlation between FATP5 and stearoyl-CoA desaturase 1 (SCD1) expression. As the rate-limiting enzyme for monounsaturated fatty acid (MUFA) biosynthesis, SCD1 overexpression exhibited ferroptosis resistance in erastin-treated HepG2 cells. Untargeted lipidomics revealed that FATP5 knockdown preferentially reduced pro-ferroptotic polyunsaturated fatty acid (PUFA)-containing lipids. Mechanistically, reduction of PUFA-lipids alleviated suppression of Sterol regulatory element binding protein 1 (SREBP1), subsequently upregulating its transcriptional target SCD1. Finally, we found that adeno-associated virus-mediated SCD1 overexpression in vivo effectively attenuated inflammation and liver injury in MASH by inhibiting hepatic ferroptosis. In conclusion, our findings suggest that FATP5 knockdown alleviates MASH via remodeling hepatic lipid composition to activate the SREBP1/SCD1 axis, thereby inhibiting ferroptosis. The findings also indicate that FATP5 may serve as a potential therapeutic target of MASH.

Ulcerative colitis (UC) is a chronic inflammatory disease characterized by impaired intestinal barrier function. Previous studies have indicated that Parabacteroides distasonis (P. distasonis) exerts a protective effect in experimental models of colitis. However, the therapeutic application of live bacteria is often hampered by inconsistent efficacy and potential safety issues. In this study, we isolated extracellular vesicles from P. distasonis (PDEV) and investigated their therapeutic potential. We provide the first demonstration that PDEV administration ameliorates disease severity in DSS-induced colitis models. Mechanistically, PDEV modulates the gut microbiota composition and host tryptophan metabolism, resulting in the accumulation of specific indole derivatives within the intestine lumen. Notably, these accumulated indole derivatives, such as indole-3-carboxaldehyde (I3A) and indole-3-propionic acid (IPA), are potent aryl hydrocarbon receptor (AhR) ligands. PDEV-induced activation of AhR was found to be crucial for the protection of the intestinal barrier against DSS-induced damage. Collectively, our results demonstrate that PDEV attenuates colitis progression primarily by enhancing AhR activation. In conclusion, our findings establish PDEV as a novel and promising biotherapeutic strategy for the management of ulcerative colitis.

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.