Yindan-Pinggan Capsules Alleviate Steatotic Liver Disease Through Modulating Multiple Signaling Pathways in Mice.

INTRODUCTION: Steatotic Liver Disease (SLD), including Alcohol-Associated Liver Disease (ALD) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), is one of the most prevalent chronic liver diseases globally, affecting approximately a quarter of the world's population. It poses a significant burden on global health, but effective treatments are limited. The Yindan-Pinggan (YDPG) formula is a modified traditional Chinese herbal remedy intended to treat liver diseases, but its role in SLD is unclear. This study aimed to explore the effects and mechanisms of YDPG against ALD and MASLD in mice. METHODS: The efficacy of YDPG was evaluated by measuring body weight and liver index and assessing hepatic steatosis via H&E and Oil Red O staining. Commercial assay kits were used to detect indicators related to liver injury, lipid metabolism, and glucose metabolism. Intraperitoneal insulin and glucose tolerance tests were performed to assess insulin homeostasis. RT-qPCR, ELISA, and Western blot analysis were applied to measure mRNA or protein expression levels. ChIP-qPCR was performed to assess PPARγ recruitment at the promoters of its target genes. RESULTS: YDPG markedly ameliorated ALD and MASLD in mice, with multiple mechanisms potentially contributing to its protective effects against SLD, which these mechanisms include: (1) inhibiting oxidative stress to mitigate hepatic injury via activation of Nrf2 signaling; (2) promoting bile salt excretion via activation of the hepatic FXR-BSEP axis; (3) suppressing hepatic lipid accumulation through dual activation of the intestinal FXR-FGF15 pathway in the ALD model; and (4) suppressing de novo lipogenesis via PPARγ-inhibition in the MASLD model. DISCUSSION: This research showed that YDPG demonstrated therapeutic potential for SLD, and the underlying mechanism of YDPG against ALD included alleviation of oxidative stress, anti-inflammatory effects, activation of the intestinal FXR-FGF15 axis, and action against MASLD via inhibition of lipogenesis in hepatocytes. These findings strengthened the evidence that YDPG could be a potential treatment strategy for SLD and offered opportunities for therapeutic advances in the field. CONCLUSION: YDPG holds potential for the treatment of ALD, likely by activating FXR and Nrf2 signaling in hepatocytes, enhancing fatty acid oxidation through the intestinal FXR-FGF15 axis, and inhibiting hepatic PPARγ signaling, which exerts a hepatic protective effect against MASLD.