Shen Xin, Feng Tingting, Li Shangbin, Wang Xingxin, Zhang Wenhui, Wang Shouyan, Zhang Xiaohan, Yang Jiguo, Liu Yuanxiang
Department of General Practice, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, 250021, China.
School of Acupuncture-Moxibustion and Tuina, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250355, China.
J Transl Autoimmun. 2025 Mar 22;10:100284. doi: 10.1016/j.jtauto.2025.100284. eCollection 2025 Jun.
Branched-chain amino acids (BCAAs), including isoleucine (Ile), leucine (Leu), and valine (Val), are substrates for synthesising nitrogenous compounds and signalling molecules involved in regulating immunity. To date, data on the role of BCAAs in autoimmune thyroiditis (AIT) are lacking; therefore, this study aimed to determine the causality using two-sample Mendelian randomisation (MR) and explored the role of BCAAs in the cGAS-STING-NLRP3 pathway .
The causal relationship between BCAAs and the pathogenesis of AIT were identified using a two-sample MR study. The anti-inflammatory effects of BCAAs and their role in the cGAS-STING-NLRP3 pathway were investigated in lipopolysaccharide (LPS)- induced thyroid follicular cells (TFCs).
Our findings indicate that BCAAs are a pathogenic factor for AIT (IVW OR = 4.960; 95 % CI = (1.54,15.940); = 0.007). Leu significantly exacerbated the inflammatory response of thyroid cells, as evidenced by the up-regulation of tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6 and down-regulation of TGF-β1; simultaneously aggravated cellular injury and oxidative stress; significantly increased the expression of Sestrin2/p-mTOR and cGAS/STING/NLRP3 in AIT cells. Furthermore, the expression of IL-18 and IL-1β was significantly increased. Conversely, Leu deprivation induced cell injury, decreased oxidative stress, and inhibited Sestrin2/p-mTOR and cGAS/STING/NLRP3 pathways.
Our findings suggest a potential causal effect of genetically predicted Leu on AIT; Leu significantly exacerbated the inflammatory response and cellular damage in AIT cells. The mechanism by which Leu induces inflammation involves activating the promoted Sestrin2/mTOR and cGAS-STING-NLRP3 signalling pathways. Our study proposes a novel mechanism for the contributions of Leu in AIT and potential therapeutic strategies involving Leu deprivation in treating AIT.
支链氨基酸（BCAAs），包括异亮氨酸（Ile）、亮氨酸（Leu）和缬氨酸（Val），是合成含氮化合物和参与调节免疫的信号分子的底物。迄今为止，关于BCAAs在自身免疫性甲状腺炎（AIT）中的作用的数据尚缺乏；因此，本研究旨在使用两样本孟德尔随机化（MR）确定因果关系，并探讨BCAAs在cGAS-STING-NLRP3通路中的作用。
使用两样本MR研究确定BCAAs与AIT发病机制之间的因果关系。在脂多糖（LPS）诱导的甲状腺滤泡细胞（TFCs）中研究BCAAs的抗炎作用及其在cGAS-STING-NLRP3通路中的作用。
我们的研究结果表明，BCAAs是AIT的致病因素（IVW OR = 4.960；95% CI =（1.54，15.940）；P = 0.007）。亮氨酸显著加剧了甲状腺细胞的炎症反应，肿瘤坏死因子-α（TNF-α）和白细胞介素（IL）-6上调以及转化生长因子-β1下调证明了这一点；同时加重了细胞损伤和氧化应激；显著增加了AIT细胞中Sestrin2/p-mTOR和cGAS/STING/NLRP3的表达。此外，IL-18和IL-1β的表达显著增加。相反，亮氨酸剥夺诱导细胞损伤，降低氧化应激，并抑制Sestrin2/p-mTOR和cGAS/STING/NLRP3通路。
我们的研究结果表明遗传预测的亮氨酸对AIT具有潜在因果效应；亮氨酸显著加剧了AIT细胞中的炎症反应和细胞损伤。亮氨酸诱导炎症的机制涉及激活促进的Sestrin2/mTOR和cGAS-STING-NLRP3信号通路。我们的研究提出了亮氨酸在AIT中的作用的新机制以及涉及亮氨酸剥夺治疗AIT的潜在治疗策略。
