Fu Xiaodi, Zhang Qi, Chen Yuhang, Li Ying, Wang Honggang
Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, Henan, China.
Mol Cell Biochem. 2025 Jun;480(6):3813-3839. doi: 10.1007/s11010-025-05220-3. Epub 2025 Feb 8.
Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide, and its exact pathogenesis has not been fully studied. Hydrogen sulfide (HS) is the third gas signaling molecule discovered in mammals, following nitric oxide and carbon monoxide. It has the effects of anti-inflammation, anti-apoptosis, and so on, thereby playing an important role in many diseases. However, the role and mechanism of exogenous HS in NAFLD are not fully understood. In this study, we constructed in vitro and in vivo NAFLD models by feeding mice a high-fat diet and stimulating hepatocytes with palmitic acid, respectively, to investigate the improvement effect and mechanism of exogenous HS on NAFLD. The results showed that NaHS (a donor of HS) treatment alleviated lipid accumulation, inflammation, apoptosis and pyroptosis, and downregulated endoplasmic reticulum (ER) stress and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NRRP3) inflammasome in NAFLD. The activation of NLRP3 inflammasome weakened NaHS improvement of NAFLD, indicating that exogenous HS ameliorated NAFLD by inhibiting NLRP3 inflammasome-mediated lipid synthesis, inflammation, apoptosis and pyroptosis. Similarly, the activation of ER stress weakened NaHS improvement of NAFLD and NaHS inhibition of NLRP3 inflammasome, indicating that exogenous HS suppressed NLRP3 inflammasome by downregulating ER stress, thus improving NAFLD. Additionally, the protein expressions of NLRP3 and cleaved caspase-1 were downregulated after inhibiting the reactive oxygen species (ROS)/extracellular signal-regulated kinases (ERK) and ROS/thioredoxin-interacting protein (TXNIP) pathways, indicating that ER stress activated NLRP3 inflammasome through the ROS/ERK and ROS/TXNIP pathways. In conclusion, our results indicated that exogenous HS inhibited NLRP3 inflammasome-mediated hepatocytes inflammation, lipid synthesis, apoptosis and pyroptosis by downregulating ER stress, thereby improving NAFLD; Furthermore, ER stress activated NLRP3 inflammasome through the ROS/ERK and ROS/TXNIP pathways in NAFLD. ER stress/NLRP3 inflammasome is expected to become a new target of HS for treating NAFLD.
非酒精性脂肪性肝病（NAFLD）是全球常见的慢性肝病，其确切发病机制尚未完全明确。硫化氢（HS）是继一氧化氮和一氧化碳之后在哺乳动物中发现的第三种气体信号分子。它具有抗炎、抗凋亡等作用，因此在许多疾病中发挥着重要作用。然而，外源性HS在NAFLD中的作用及机制尚未完全清楚。在本研究中，我们分别通过给小鼠喂食高脂饮食和用棕榈酸刺激肝细胞构建了体外和体内NAFLD模型，以研究外源性HS对NAFLD的改善作用及机制。结果表明，NaHS（一种HS供体）处理减轻了NAFLD中的脂质蓄积、炎症、凋亡和焦亡，并下调了内质网（ER）应激和含吡咯结构域的核苷酸结合寡聚化结构域样受体3（NRRP3）炎性小体。NLRP3炎性小体的激活减弱了NaHS对NAFLD的改善作用，表明外源性HS通过抑制NLRP3炎性小体介导的脂质合成、炎症、凋亡和焦亡来改善NAFLD。同样，ER应激的激活减弱了NaHS对NAFLD的改善作用以及NaHS对NLRP3炎性小体的抑制作用，表明外源性HS通过下调ER应激来抑制NLRP3炎性小体，从而改善NAFLD。此外，在抑制活性氧（ROS）/细胞外信号调节激酶（ERK）和ROS/硫氧还蛋白相互作用蛋白（TXNIP）途径后，NLRP3和裂解的半胱天冬酶 -1的蛋白表达下调，表明ER应激通过ROS/ERK和ROS/TXNIP途径激活NLRP3炎性小体。总之，我们的结果表明，外源性HS通过下调ER应激抑制NLRP3炎性小体介导的肝细胞炎症、脂质合成、凋亡和焦亡，从而改善NAFLD；此外，在NAFLD中，ER应激通过ROS/ERK和ROS/TXNIP途径激活NLRP3炎性小体。ER应激/NLRP3炎性小体有望成为HS治疗NAFLD的新靶点。
