Tetramethylpyrazine: A fermented alcohol product that mitigates alcoholic liver disease in mice

Alcoholic liver disease (ALD) is a leading cause of premature death globally yet remains under-controlled. In this study, we investigated the protective effects of tetramethylpyrazine (TMP), an aromatic compound found in fermented alcohol, against ALD in a National Institute on Alcohol Abuse and Alcoholism (NIAAA) mice model. Our results demonstrated that TMP significantly reduced alcohol-induced liver injury, steatosis, oxidative stress, and mitochondrial damage, while restoring NAD⁺ levels and the NAD⁺/NADH ratio, increasing ATP production, regulating energy metabolism disorders, and restoring metabolic balance (P < 0.05). Liver transcriptomic analysis identified 906 ALD-associated genes enriched in energy and lipid metabolism pathways, with a molecular signature of NAD-dependent oxidoreductase activity. Protein interaction analysis predicted Nicotinamide Phosphoribosyltransferase (NAMPT) as a key rate-limiting enzyme in NAD metabolism. Cellular Thermal Shift Assay (CETSA) experiments and molecular docking studies further confirmed that TMP can restore the level of NAD⁺ by stabilizing the NAMPT protein. TMP is present in various foods, including Semen Sojae Preparatum, a TMP-rich fermented food commonly used in Traditional Chinese Medicine for ALD treatment. This food exhibited significant protective effects against ALD. In conclusion, TMP, an aromatic compound in fermented alcohol, could protect the liver from alcohol-induced damage. Enhancing TMP content in fermented alcohol holds significant promise for mitigating the adverse effects of alcohol consumption on the liver.