Although fulminant hepatitis represents a ubiquitous human health problem, there is a lack of effective therapeutic strategies that have few side‑effects and the precise mechanisms underlying fulminant hepatitis are not fully understood. Phosphoinositide 3‑kinase (PI3K) is a pivotal kinase known to regulate inflammatory responses in hepatic diseases. Although previous research indicates that PI3K is involved in cardiac diseases, including myocardial infarction, it currently remains unclear whether the inhibition of PI3K is essential for ameliorating the severity of lipopolysaccharide (LPS)‑induced hepatitis. The aim of the present study was to investigate whether pharmacological blockade of PI3K ameliorates the development of LPS‑induced murine acute hepatic injury. A murine model of LPS‑induced acute hepatic injury was used to investigate the therapeutic effect of the pan‑PI3K inhibitor, LY294002 on murine fulminant hepatitis and to investigate potential underlying mechanisms. The current report presents the in vivo role of LY294002 in protecting the mice from fulminant hepatitis. LY294002 was observed to exert significant protective effects on the liver by reducing the activities of alanine aminotransferase and aspartate aminotransferase, as well as by improving the histological architecture of the liver. In LPS‑induced hepatitis, treatment with LY294002 clearly inhibited intrahepatic synthesis of various disease‑relevant proinflammatory cytokines, including tumor necrosis factor‑α, interleukin (IL)‑6, IL‑1β and interferon‑γ. Furthermore, LY294002 was observed to significantly inhibit IκB phosphorylation in LPS‑injured mouse liver samples. Therefore, LY294002 may protect the liver from LPS‑induced injury by inhibition of the IκB‑nuclear factor κ‑light‑chain‑enhancer of activated B cell dependent signaling pathway. Thus, the current report provides evidence that LY294002 exerts potent effects against LPS‑induced hepatic injury, indicating its potential therapeutic value for the treatment of acute hepatitis.

(1) SAH induces cellular stress and endoplasmic reticulum stress, activating the unfolded protein response (UPR) in nerve cells. IRE1 (inositol-requiring enzyme 1) is a protein that plays a critical role in cellular stress response. Its final product, Xbp1s, is essential for adapting to changes in the external environment. This process helps maintain proper cellular function in response to various stressors. O-GlcNAcylation, a means of protein modification, has been found to be involved in SAH pathophysiology. SAH can increase the acute O-GlcNAcylation level of nerve cells, which enhances the stress capacity of nerve cells. The GFAT1 enzyme regulates the level of O-GlcNAc modification in cells, which could be a potential target for neuroprotection in SAH. Investigating the IRE1/XBP1s/GFAT1 axis could offer a promising avenue for future research. (2) Methods: SAH was induced using a suture to perforate an artery in mice. HT22 cells with Xbp1 loss- and gain-of-function in neurons were generated. Thiamet-G was used to increase O-GlcNAcylation; (3) Results: Severe neuroinflammation caused by subarachnoid hemorrhage leads to extensive endoplasmic reticulum stress of nerve cells. Xbp1s, the final product of unfolded proteins induced by endoplasmic reticulum stress, can induce the expression of the hexosamine pathway rate limiting enzyme GFAT1, increase the level of O-GlcNAc modification of cells, and have a protective effect on neural cells; (4) Conclusions: The correlation between Xbp1s displayed by immunohistochemistry and O-GlcNAc modification suggests that the IRE1/XBP1 branch of unfolded protein reaction plays a key role in subarachnoid hemorrhage. IRE1/XBP1 branch is a new idea to regulate protein glycosylation modification, and provides a promising strategy for clinical perioperative prevention and treatment of subarachnoid hemorrhage.