Deletion of cyclooxygerase-2 in macrophages amplifies diet-induced metabolic dysfunction-associated steatohepatitis (MASH) in mice

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising rapidly. In the severe form of steatohepatitis (MASH), steatosis is accompanied by an infiltration of immune cells, inflammatory processes and beginning fibrosis, which increases the risk of developing hepatocellular carcinoma. Cyclooxygenase-2 (COX-2)-dependent generated lipid mediators such as prostaglandin E2 are mainly expressed in macrophages and play pivotal roles in cell communication. The aim of the study was to clarify the inflammatory role of COX-2 in diet-induced MASH. Mice with macrophage-specific COX-2-deficiency fed a MASH-inducing diet gained more body and liver weight, and were more insulin resistant than controls receiving the same diet. Liver histology revealed MASH-diagnosis in all mice fed the MASH-inducing Western diet. Hepatic steatosis and parameters for hepatic inflammation such as infiltration of F4/80-positive immune cells and expression of pro-inflammatory cytokines and immune cell recruiting chemokines were more enhanced in mice livers with COX-2 deletion than in controls. COX-2-derived prostaglandin E2 inhibited TNF-α-synthesis and modulation of this feedback inhibition in transgenic mice resulted in higher hepatic levels of this pro-inflammatory cytokine. The current study indicated a protective role of COX-2 in the development of diet-induced MASH. Inhibition of COX-2 might be harmful in MASH progression since the COX-2-deletion in macrophages aggravated the diet-induced steatohepatitis in transgenic mice mainly by enhancing the TNF-α-triggered inflammatory response. Publication History Article published online: 26 January 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany