Niacin alleviates extracellular matrix deposition in ethanol + CCl4-induced liver fibrosis through the HSP90/JAK1/STAT3 axis

Abstract

Alcoholic liver fibrosis (ALF) is a reversible pathological change in the liver caused by chronic alcohol consumption and is associated with the activation of hepatic stellate cells. Recent findings suggest that niacin can lower triglyceride levels and exert potent antioxidant effects in liver damage. However, the therapeutic effects and molecular mechanisms of niacin in liver fibrosis remain unclear. Therefore, this study aimed to investigate the effects and mechanisms of niacin in ALF using in vivo and in vitro experiments. To establish a murine model of ALF, male C57BL/6N mice were fed a Lieber–DeCarli liquid diet containing 4 % (vol/vol) ethanol and injected with carbon tetrachloride twice weekly (2 mL/kg) for 8 weeks. L-02 and LX2 cells were treated with 400 μM acetaldehyde for 24 h to establish an in vitro ALF model. Serum parameters were examined to investigate the protective effects of niacin against ALF, and network pharmacology was used to identify potential targets and pathways of niacin. Niacin protects against ALF by suppressing the serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and alkaline phosphatase. Additionally, niacin treatment ameliorated liver fibrosis by improving the antioxidant system, inhibiting heat shock protein 90 (HSP90) activation, promoting signal transducer and activator of transcription 3 (STAT3) ubiquitination, and suppressing the JAK1/STAT3 signaling pathway. Collectively, this study provides experimental evidence that niacin protects against ALF by downregulating the HSP90/JAK1/STAT3 signaling pathway.