Liver fibrosis is characterized by the excessive accumulation of extracellular matrix proteins, which can lead to cirrhosis and liver cancer. Metabolic dysfunction-associated steatosis liver diseases are common causes of liver fibrosis, sharing a similar pathogenesis with carbon tetrachloride (CCl₄) exposure. This process involves the activation of hepatic stellate cells (HSCs) into myofibroblasts. However, the detailed mechanism and effective treatment strategies require further investigation. In this study, we uncovered a negative correlation between VDR expression and YAP within HSCs. Subsequently, we demonstrated that VDR exerted a downregulatory influence on YAP transcriptional activity in HSCs. Intriguingly, activation VDR effectively inhibited the culture induced activation of primary HSCs by suppressing the transcriptional activity of early YAP. Furthermore, results manifested that hepatic-specific deletion of YAP/TAZ ameliorates CCl-induced liver fibrosis, and nullified the antifibrotic efficacy of VDR. Importantly, a YAP inhibitor rescued the exacerbation of liver fibrosis induced by hepatic-specific VDR knockout. Moreover, the combined pharmacological of VDR agonist and YAP inhibitor demonstrated a synergistic effect in diminishing CCl-induced liver fibrosis, primary HSCs activation and hepatic injury . These effects were underpinned by their collective ability to inhibit HSC activation through AMPK activation, consequently curbing ATP synthesis and HSCs proliferation. In conclusion, our results not only revealed the inhibition of VDR on YAP-activated liver stellate cells but also identified a synergistic effect of VDR agonist and YAP inhibitor in an AMPKα-dependent manner, providing a practical foundation for integration of multi-targeted drugs in the therapy of CCl-induced hepatic fibrosis.

中文翻译：

---

维生素 D 受体通过下调 YAP 减轻四氯化碳诱导的肝纤维化


肝纤维化的特点是细胞外基质蛋白过度积累，可导致肝硬化和肝癌。代谢功能障碍相关的脂肪变性肝病是肝纤维化的常见原因，与四氯化碳（CCl₄）暴露具有相似的发病机制。这个过程涉及肝星状细胞（HSC）活化成肌成纤维细胞。然而，详细的机制和有效的治疗策略还需要进一步研究。在这项研究中，我们发现 HSC 内 VDR 表达与 YAP 之间呈负相关。随后，我们证明 VDR 对 HSC 中 YAP 转录活性产生下调影响。有趣的是，激活VDR通过抑制早期YAP的转录活性，有效抑制培养物诱导的原代HSC的激活。此外，结果表明，YAP/TAZ 的肝脏特异性缺失可改善 CCl 诱导的肝纤维化，并抵消 VDR 的抗纤维化功效。重要的是，YAP 抑制剂可以挽救因肝脏特异性 VDR 敲除引起的肝纤维化恶化。此外，VDR激动剂和YAP抑制剂的联合药理学显示出在减少CCl诱导的肝纤维化、原发性HSC活化和肝损伤方面具有协同作用。这些作用的基础是它们通过 AMPK 激活抑制 HSC 激活的集体能力，从而抑制 ATP 合成和 HSC 增殖。 总之，我们的结果不仅揭示了VDR对YAP激活的肝星状细胞的抑制作用，而且还确定了VDR激动剂和YAP抑制剂以AMPKα依赖的方式产生协同作用，为多靶点药物在肝星状细胞中的整合提供了实用基础。 CCl诱导的肝纤维化的治疗。