Fused Azine Derivatives Mitigate Long-Term Paracetamol-Induced Liver Fibrosis in Mice: Role of JNK1/ASK1 and Nrf2/HO-1 Signaling Pathways

Liver fibrosis is a significant public health issue that necessitates an ongoing urge for efficient novel treatments. Our newly synthesized fused azine derivative compounds (1a, 1b, 2a, and 2b) were used in this study based on our promising results achieved by our team in previous studies on tacrine derivatives. This study investigated these compounds’ hepatoprotective effect on mice with paracetamol (APAP) induced liver fibrosis and clarified their possible mechanisms. The administration of these compounds successfully reduced APAP-induced hepatic fibrosis through decreasing serum liver enzymes, as well as the hepatic pathological deterioration. Moreover, they increased hepatic antioxidants and countered oxidative stress caused by APAP. Furthermore, by lowering inflammatory cytokine levels and raising anti-inflammatory marker levels, these compounds effectively ameliorated the inflammatory response. Additionally, they decreased APAP induced levels of apoptosis-signal-regulating kinase-1 (ASK-1) and c-Jun-N-terminal kinase (JNK1). Additionally, they reduced caspase-3 and BCL2-associated X-protein (Bax) levels and promoted Nrf2 signaling pathway activation. Notably, the in-silico computer-assisted simulation docking results were consistent with the experimental measurements.