Inhibition of store-operated calcium entry mitigates lipopolysaccharide-induced hepatotoxicity via modulating inflammatory and oxidative stress responses.

Abstract

IntroductionHepatotoxicity can arise secondary to several medical conditions, including inflammation, sepsis, and therapy. Lipopolysaccharide (LPS) can activate diverse inflammatory pathways and has been implicated in hepatotoxicity. The store-operated calcium entry (SOCE), a key process for maintaining cellular calcium homeostasis, was shown to modulate inflammatory signaling. Reactive oxygen species, which serve a significant role in maintaining cellular function and homeostasis, are often elevated during inflammation, contributing to tissue injury. Therefore, we hypothesized that blocking the SOCE pathway would inhibit LPS-induced hepatotoxicity by suppressing inflammation and oxidative stress.MethodsTo test this, female BALB/c mice were randomly divided into the following experimental groups: control, LPS, LPS + SOCE inhibitor 2-aminoethoxy diphenyl borate (2APB), and 2APB alone. After 24 h of treatment, serum and liver samples were collected from the mice for histopathological, biochemical, and molecular analyses.ResultsInhibition of SOCE led to a decrease in the elevated liver function enzymes (ALT and AST) and protected the liver parenchymal cells as observed by histopathological assessment. Furthermore, blockade of SOCE significantly suppressed the level of il-1b, il-6, and cox2 genes in the liver tissues of mice treated with LPS. The expression of antioxidant genes (gsta1 and gpx1) was also significantly reduced by LPS treatment, while SOCE inhibition only restored the gpx1 expression. Additionally, treatment with 2APB attenuated LPS-induced oxidative stress in the liver of mice.ConclusionCollectively, our work demonstrated the critical involvement of SOCE in regulating inflammation and oxidative stress associated with LPS treatment, thereby reducing hepatotoxicity.