Hepatoprotective Effects of Gac (Momordica cochinchinensis) Aril Extract in Acetaminophen-Induced Liver Injury: Modulation of Oxidative Stress, Inflammation, and Glucose Metabolism

N-acetyl-p-aminophenol (APAP) overdose remains a leading cause of acute liver failure worldwide. The aril extracts derived from Gac (Momordica cochinchinensis) (MC) fruit contain diverse phytonutrients that exhibit a range of pharma-nutritional properties, including antioxidant and anti-hepatic damage properties. Despite the therapeutic potential, the molecular mechanisms underlying its hepatoprotective action, particularly in preventing drug-induced toxicity, remain unelucidated. This study investigated the hepatoprotective potential of MC in a mouse model of APAP-induced acute liver injury and characterized its bioactive compounds. MC was prepared using aqueous extraction. Mice were pre-treated with either 500 or 1,000 mg/kg of MC for seven consecutive days prior to intraperitoneal administration of APAP 300 mg/kg to induce hepatotoxicity. Serum and liver samples were then collected to analyze biochemical changes, histopathological changes, oxidative stress markers, and/or mRNA expression. Standard chemical tests were used to identify bioactive compounds. APAP administration caused a marked rise in liver enzymes, extensive histological necrosis, suppression of hepatocyte proliferation, infiltration of neutrophils and macrophages, and significant oxidative damage (p < 0.05). Studies revealed the constitution of MC as phenolic compounds, flavonoids, proanthocyanidins, and ascorbic acid, significantly attenuated the hepatotoxicity (p < 0.05). Mechanistically, MC ameliorated hepatic mRNA expression of CYP2E1, JNK, Ddit3, Bax, Casp3, NF-κB, and MCP-1, while increasing Bcl-2, IL-10, VEGF, Nrf2, SOD2, and GCLC mRNA (p < 0.05). Furthermore, MC prevented hyperglycemia by influencing the expression of AdipoR1, GLUT-2, and PEPCK (p < 0.05). MC exhibits hepatoprotective effects against APAP-induced liver injury through multifaceted modulation of toxic metabolism (CYP2E1), cell death and ER stress (JNK, Ddit3, Bax, Casp3, and Bcl-2), antioxidant response (Nrf2 pathway), inflammation (NF-κB pathway and IL-10), tissue repair (VEGF), and glucose metabolism (AdipoR1, GLUT-2, and PEPCK).