Thymoquinone is effective in thioacetamide-induced liver damage via the RIP1/RIP3/MLKL axis.

Impaired regenerative capacity following liver damage affects tissue functionality and forms the basis of diseases such as fibrosis, cirrhosis, and carcinoma. This study aimed to induce thioacetamide (TAA)-induced liver damage and to investigate the effect of thymoquinone (THQ) through receptor-interacting kinases (RIP/RIPK) and various other mechanisms. Study design: Control, TAA (2 doses 300 mg/kg), TAA + THQ10 (2 doses 300 mg/kg TAA + 10 mg/kg THQ), TAA + THQ20 (2 doses 300 mg/kg TAA + 20 mg/kg THQ), TAA + THQ40 (2 doses 300 mg/kg TAA + 40 mg/kg THQ). Histologically, hepatocyte degeneration, inflammatory cell infiltration, necrosis, glycogen accumulation, and collagen density were semi-quantitatively scored. α-SMA, TNF-α, RIP1, RIP3 and MLKL expression levels were determined. AST, ALT, and GGT levels in blood serum, and TGF-ß1, MMP-7, MMP-9, MMP-13, and TIMP1 levels in liver tissue homogenate were examined using ELISA. TAA increased liver AST, ALT, and GGT levels, α-SMA and TNF-α gene and protein expression, necroptosis markers RIP3 and MLKL, in addition to histopathological necrosis, and TGF-β1 and MMP-7 levels. While it was shown that THQ doses (20 and 40 mg/kg) may have therapeutic effects on these parameters, the effect of TAA on liver damage, specifically necrotic tissue damage, was demonstrated in this study not through histopathological evidence, but through increased necroptosis markers RIP3 and MLKL. It has been suggested that TAA may achieve this effect through the presence of increased TNF-α and TGF-β1, and the resulting oxidative stress, which alters MMPs in the tissue. New findings indicate that THQ, at doses of 20 and 40 mg/kg, can exhibit therapeutic effects in tissue.