PO.MCB09.02 · 分子与细胞生物学
靶向DYRK1A调控的脂肪生成-STING轴减轻代谢性脂肪性肝炎中的肝脏代谢功能障碍和脂毒性
Targeting a DYRK1A-regulated lipogenesis-STING axis alleviates hepatic metabolic dysfunction and lipotoxicity in metabolic steatohepatitis
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：代谢功能障碍相关脂肪性肝炎（MASH）是一种进行性肝病，以脂质积累、炎症和纤维化为特征，可进展为肝细胞癌。虽然从头脂肪生成（DNL）和固有免疫激活均驱动疾病进展，但它们之间的机制联系仍不清楚。在此，我们鉴定DYRK1A为一种新型激酶，可激活STING依赖性炎症信号传导，并在MASH中连接代谢和免疫失调。
方法：在细胞和动物系统中均建立了MASH和纤维化模型。通过敲低、过表达和药理学抑制调控DYRK1A表达。使用分子检测、组织病理学和血清损伤标志物评估脂肪生成、STING激活、脂毒性和纤维化。
结果：与对照相比，MASH细胞模型中DYRK1A表达升高约40%。此外，我们证实DYRK1A过表达降低了AMPK和ACC的磷酸化，增强脂肪生成通量并提高脂质积累，支持其可能参与代谢调节。相反，DYRK1A沉默或抑制剂处理抑制了DNL，使STING失稳，并通过降低STING、TBK1和IRF3的磷酸化减轻脂毒性，这经油红O染色和免疫印迹证实。在体内，DYRK1A在MASH相关纤维化中显著升高，而其抑制降低了肝脏甘油三酯沉积（约30%）、胶原重塑（约30%）和血清AST/ALT水平（约40%），表明肝功能改善。与体外结果一致，抑制剂处理的肝脏表现出DNL和STING相关蛋白表达减少，突显DYRK1A为一种新鉴定的代谢性炎症和纤维化的关键驱动因素。
结论：本研究定义了一种新型DYRK1A介导的脂肪生成-炎症级联反应，将代谢应激与MASH中的固有免疫激活和纤维化相联系。靶向DYRK1A可能提供一种治疗策略，以破坏脂肪生成-STING轴、减轻慢性代谢性肝损伤，并可能预防进展为肝细胞癌。
查看英文原文 English abstract
Background Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease marked by lipid accumulation, inflammation, and fibrosis that can advance to hepatocellular carcinoma. While both de novo lipogenesis (DNL) and innate immune activation drive disease progression, their mechanistic connection remains unclear. Here, we identified DYRK1A as a novel kinase that activates STING-dependent inflammatory signaling and links metabolic and immune dysregulation in MASH.
Methods MASH and fibrosis models were established in both cellular and animal systems. DYRK1A expression was modulated through knockdown, overexpression, and pharmacological inhibition. Lipogenesis, STING activation, lipotoxicity, and fibrosis were assessed using molecular assays, histopathology, and serum injury markers.
Results DYRK1A expression was elevated by approximately 40% in cellular models of MASH compared with controls. Further, we confirmed DYRK1A overexpression reduced phosphorylation of AMPK and ACC, enhancing lipogenic flux and elevating lipid accumulation, supporting its potential involvement in metabolic regulation. Conversely, DYRK1A silencing or inhibitor treatment suppressed DNL, destabilized STING, and mitigated lipotoxicity by reducing the phosphorylation of STING, TBK1 and IRF3, as confirmed by Oil Red O staining and immunoblotting. In vivo , DYRK1A was markedly elevated in MASH-associated fibrosis, whereas its inhibition reduced hepatic triglyceride deposition (~30%), collagen remodeling (~30%), and serum AST/ALT levels (~40%), indicating improved liver function. Consistent with in vitro results, inhibitor-treated livers exhibited diminished DNL- and STING-related proteins expression, underscoring DYRK1A as a newly identified key driver of metabolic inflammation and fibrosis.
Conclusions This study defines a novel DYRK1A-mediated lipogenic-inflammatory cascade linking metabolic stress to innate immune activation and fibrosis in MASH. Targeting DYRK1A may provide a therapeutic strategy to disrupt the lipogenesis-STING axis, alleviate chronic metabolic liver injury, and potentially prevent progression to hepatocellular carcinoma.
利益披露 Disclosure
W. Huang, None..
K. Noh, None.