Honokiol Ameliorates LPS/D-GalN-Induced Acute Liver Failure via Activation of SIRT3/AMPK and Keap1/Nrf2/HO-1 Signaling and Inhibition of the NF-κB/NLRP3 Inflammasome Axis

Background/Objectives: Abrupt impairment of liver functions, extensive hepatocellular necrosis, and high short-term mortality in patients without pre-existing liver disease are characteristic hallmarks of acute liver failure (ALF). Therapeutic options for ALF remain extremely limited, with liver transplantation representing the only definitive intervention in advanced cases, highlighting the urgent need for effective pharmacological strategies to limit early hepatic injury and disease progression. Honokiol (HON), a biphenolic lignan derived from Magnolia species, possesses documented antioxidant and anti-inflammatory properties; however, its protective potential and mechanisms in ALF remain incompletely defined. Methods: A lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced ALF murine model was employed to explore the hepatoprotective potential of HON (5 and 10 mg/kg) and its possible underlying mechanisms. Results: HON pretreatment significantly (i) attenuated hepatocellular injury, as evidenced by marked reductions in serum liver enzyme levels and suppression of necroinflammation and neutrophil infiltration. HON also (ii) restored hepatic redox homeostasis by enhancing antioxidant defenses and reducing lipid peroxidation and nitrosative stress. These effects were accompanied by (iii) activation of the Keap1/Nrf2/HO-1 signaling axis; (iv) suppression of NF-κB activation with subsequent inhibition of NLRP3 inflammasome and caspase-1 activation; and (v) reduction in hepatic TNF-α, IL-1β, and IL-18 levels. In parallel, HON (vi) restored mitochondrial SIRT3 and AMPK signaling. Conclusions: Our findings demonstrate that HON effectively protects against LPS/D-GalN-induced ALF via coordinated enhancement of antioxidant defense and suppression of inflammatory signaling pathways, supporting its potential as a promising pleiotropic therapeutic candidate for ALF.