羟基藏红花黄素A（HSYA）是胡麻花（Carthamus tinctorius L.）的一种川芎烯苷，具有抗炎和抗氧化功效，然而，HSYA在治疗溃疡性结肠炎方面的治疗效果和潜在机制还不清楚。本研究旨在研究HSYA对UC的保护作用及其潜在机制。体外分析显示，HSYA减少了脂多糖/三磷酸腺苷（LPS/ATP）刺激的巨噬细胞分泌白细胞介素（IL）-1β、肿瘤坏死因子（TNF）-α和IL-6，抑制了核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）/气体通道形成素D（GSDMD）介导的火力症状。气相色谱-质谱（GC-MS）分析细胞内代谢物的谱带显示，HSYA减少了糖、葡萄糖6磷酸和乳酸水平的升高，抑制了LPS/ATP刺激引起的HK1表达升高。转染HK1 shRNA进一步证实HSYA通过HK1下调抑制NLRP3/GSDMD介导的火山岩石，从而起到抗炎作用。体内分析显示，HSYA通过减轻体重下降、结肠长度下降和DSS（硫酸葡聚糖）诱导的结肠组织炎性浸润，显着减轻了UC症状。HSYA还减少了IL-1β、IL-6、TNF-α和IL-18等前炎症因子分泌。此外，HSYA抑制了DSS诱导的结肠炎小鼠中HK1/NLRP3/GSDMD介导的火化现象。最后，对肠道菌群的16S rRNA测序分析表明，HSYA通过减少变形菌门的数量和增加拟杆菌门的数量来逆转肠道菌群失调。本研究表明，HSYA不仅通过抑制HK1/NLRP3/GSDMD和抑制火力症的方式发挥抗炎作用，而且还调节了DSS诱导的结肠炎小鼠的肠道菌群。我们的发现为HSYA成为治疗炎性肠病的潜在药物提供了新的实验证据。版权所有©2023 Elsevier Inc.

Hydroxysafflor yellow A (HSYA), a chalcone glycoside, is a component of Carthamus tinctorius L. and exerts anti-inflammatory and antioxidative effects. However, the therapeutic effect and the underlying mechanism of HSYA on ulcerative colitis is unclear. This study aimed to investigate the unexplored protective effects and underlying mechanisms of HSYA on UC. In vitro analyses showed that HSYA reduced the secretion of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 and inhibited nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3)/gasdermin D (GSDMD)-mediated pyroptosis in lipopolysaccharide/ adenosine-5'-triphosphate (LPS/ATP)-stimulated macrophages. Gas chromatography-mass spectrometry (GC-MS) profiling of intracellular metabolites showed that HSYA reduced the increased levels of glucose, glucose 6-phosphate, and lactic acid, and inhibited the increased hexokinase 1 (HK1) expression caused by LPS/ATP stimulation. HK1 shRNA transfection further confirmed that HSYA inhibited the NLRP3/GSDMD-mediated pyroptosis via HK1 downregulation. In vivo analyses showed that HSYA drastically attenuated UC symptoms by relieving body weight loss, a decline in colon length, and inflammatory infiltration in colonic tissues induced by DSS (dextran sulfate sodium). HSYA also reduced the secretion of pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, and IL-18. Moreover, HSYA inhibited HK1/NLRP3/GSDMD-mediated pyroptosis in DSS-induced colitis mice. Finally, 16S rRNA sequencing analyses of gut microbiota revealed that HSYA reversed gut microbiota dysbiosis by reducing the abundance of Proteobacteria and increasing that of Bacteroidetes. This study demonstrated that HSYA not only exerted anti-inflammatory effects by inhibiting HK1/NLRP3/GSDMD and suppressing pyroptosis but also regulated gut microbiota in mice with DSS-induced colitis. Our findings provide new experimental evidence that HSYA might be a potential candidate for treating inflammatory bowel diseases.Copyright © 2023. Published by Elsevier Inc.