Limonin Attenuates LPS-Induced Hepatotoxicity by Inhibiting Pyroptosis via NLRP3/Gasdermin D Signaling Pathway

Abstract

Lipopolysaccharide (LPS)-induced liver injury is the main factor in acute liver failure. The current study aims to investigate the protection of limonin, an antioxidant compound from citrus fruit, against LPS-induced liver toxicity and elucidate the potential mechanisms. We found that limonin elevated cell viability and reduced LDH release in LPS-treated HepG2 cells. Limonin also inhibited LPS-induced pyroptosis by inhibiting membrane rupture, reducing ROS generation, and decreasing gasdermin D activation. Moreover, limonin inhibited the formation of a NOD-like receptor protein 3 (NLRP3)/Apoptosis-associated speck-like protein containing a CARD (ASC) complex by reducing the related protein expression and the colocalization cytosolic of NLRP3 and caspase-1 and then suppressed IL-1β maturation. Ultimately, we established LPS-induced hepatotoxicity in vivo by using C57BL/6 mice administrated LPS (10 mg/kg) intraperitoneally and limonin (50 and 100 mg/kg) orally. We found that limonin dereased the serum ALT and AST activity and LDH release and increased the hepatic GSH amount in LPS-treated mice. Additionally, the liver histological evaluation revealed that limonin protects against LPS-induced liver damage. We further demonstrated that limonin ameliorated LPS-induced hepatotoxicity by inhibiting pyroptosis via the NLRP3/gasdermin D signaling pathway. In summary, this study uncovered the mechanism whereby limonin mitigated LPS-induced hepatotoxicity and documented that limonin might be a promising candidate drug for LPS-induced hepatotoxicity.

Limonin Alleviates Non-alcoholic Fatty Liver Disease by Reducing Lipid Accumulation, Suppressing Inflammation and Oxidative Stress

“…However, the pathogenesis of NAFLD has not yet been fully elucidated, and the determination of therapeutic targets and the advancement of drug development are severely limited. Current research shows that limonin has a wide range of pharmacological effects, including anti-cancer, anti-inflammation, anti-bacterial, anti-viral, anti-oxidation and liver protection properties ( Fan et al, 2019 ), and has been proven to have the effect of preventing and treating alcoholic fatty liver ( Valansa et al, 2020 ) and various acute liver injuries ( Mahmoud et al, 2014a ; Mahmoud et al, 2014b ; Yang et al, 2021 ). But the therapeutic potential of limonin in NAFLD is still unknown.…”

Computational studies on the interaction of SARS-CoV-2 Omicron SGp RBD with human receptor ACE2, limonin and glycyrrhizic acid

“…The literatures supported the importance of phytochemicals in formulating adjuvant therapeutic approaches to fight against SARS-CoV-2 [ 21 , 22 ]. The therapeutic nature of the limonoids and triterpenoids based phytochemicals like limonin, glycyrrhizic acid, maslinic acid, obacunone,7-deacetyl-7-benzoylgedunin, corosolic acid and ursolic acid was well-known against HIV-1, SARS-CoV, cancers, and other viral and fungal infections [ [23] , [24] , [25] , [26] ]. Also, our recent results supported the role of limonoids and triterpenoids against therapeutic protein targets of SARS-CoV-2, such as spike glycoprotein, RdRp, PLpro, 3CLpro, NSP13, NSP14 and NSP15 as well as host receptors ACE2, furin and TMPRSS2 involved in the host-pathogen interactions [ 27 , 28 ].…”

11S Glycinin Up-Regulated NLRP-3-Induced Pyroptosis by Triggering Reactive Oxygen Species in Porcine Intestinal Epithelial Cells

“…NOD-like receptor protein 3 (NLRP-3) is a protein complex in cells. Its main function is to activate caspase-1, activated caspase-1 cleaves gasdermin D (GSDMD), induces pyroptosis and promotes the secretion of interleukin-1β (IL-1β), causing an inflammatory response ( 17 , 18 ).…”