Yi Wendan, Wang Haiyue, Liu Sijie, Zhang Jingjing, Ji Yiqing, Wang Haowen, Zhao Xintong, Chen Jiajun, Luo Wenjuan
Department of Ophthalmology, The Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Clinical Medicine, First College of Clinical Medicine, Binzhou Medical University, Yantai, China.
Invest Ophthalmol Vis Sci. 2025 Jul 1;66(9):43. doi: 10.1167/iovs.66.9.43.
6-Shogaol (6-S) has demonstrated anti-inflammatory effects in various disease models; however, its effects in uveitis have not been investigated. This research intends to investigate the therapeutic mechanisms of 6-S in acute uveitis.
An endotoxin-induced uveitis (EIU) mouse model was developed to assess the therapeutic potential of 6-S for uveitis. Disease severity was evaluated through anterior segment evaluation, clinical scoring, and pathology staining. RNA sequencing (RNA-seq) and network pharmacology explored the potential molecular mechanisms. In vitro, BV2 cells were stimulated by lipopolysaccharide. The mRNA and protein levels of pro-inflammatory cytokines, endoplasmic reticulum (ER) stress markers, and hypoxia-inducible factor 1-alpha (HIF-1α) in eyeballs and cells were detected. Transmission electron microscopy and Ca2+ levels were used to evaluate ER damage. The targeting effect of 6-S on HIF-1α was tested by HIF-1α siRNA.
6-S alleviated EIU in mice. RNA-seq indicated that inflammatory pathways are potential mechanisms of 6-S treatment. Further results showed that 6-S inhibited the expression of pro-inflammatory cytokines in vivo and in vitro. Network pharmacology revealed that the effect of 6-S may related to the ER. 6-S downregulated GRP78, ATF4, and CHOP expression; suppressed PERK and IRE1α phosphorylation; and mitigated ER swelling and cellular Ca2+ overload. Moreover, 6-S upregulated the expression of HIF-1α in vivo and in vitro. Inhibiting HIF-1α largely eliminated the anti-inflammatory and relieving ER stress properties of 6-S.
6-S alleviates ER stress and inflammatory responses by modulating the expression of HIF-1α, thereby improving the prognosis of EIU.
6-姜辣素（6-S）已在多种疾病模型中显示出抗炎作用；然而，其在葡萄膜炎中的作用尚未得到研究。本研究旨在探讨6-S治疗急性葡萄膜炎的机制。
建立内毒素诱导的葡萄膜炎（EIU）小鼠模型，以评估6-S对葡萄膜炎的治疗潜力。通过眼前节评估、临床评分和病理染色来评估疾病严重程度。RNA测序（RNA-seq）和网络药理学探索潜在的分子机制。在体外，用脂多糖刺激BV2细胞。检测眼球和细胞中促炎细胞因子、内质网（ER）应激标志物和缺氧诱导因子1α（HIF-1α）的mRNA和蛋白水平。用透射电子显微镜和钙离子水平评估内质网损伤。用HIF-1α siRNA检测6-S对HIF-1α的靶向作用。
6-S减轻了小鼠的EIU。RNA-seq表明炎症途径是6-S治疗的潜在机制。进一步的结果表明，6-S在体内和体外均抑制促炎细胞因子的表达。网络药理学显示，6-S的作用可能与内质网有关。6-S下调GRP78、ATF4和CHOP的表达；抑制PERK和IRE1α的磷酸化；减轻内质网肿胀和细胞内钙离子过载。此外，6-S在体内和体外均上调HIF-1α的表达。抑制HIF-1α在很大程度上消除了6-S的抗炎和减轻内质网应激的特性。
6-S通过调节HIF-1α的表达减轻内质网应激和炎症反应，从而改善EIU的预后。
