The endoplasmic reticulum (ER) is determinant to maintain cellular proteostasis. Upon unresolved ER stress, this organelle activates the unfolded protein response (UPR). Sustained UPR activates is known to occur in inflammatory processes, deeming the ER a potential molecular target for the treatment of inflammation. This work characterizes the inflammatory/UPR-related molecular machinery modulated by an in-house library of natural products, aiming to pave the way for the development of new selective drugs that act upon the ER to counter inflammation-related chronic diseases. Starting from a library of 134 compounds of natural occurrence, mostly occurring in medicinal plants, nontoxic molecules were screened for their inhibitory capacity against LPS-induced nuclear factor kappa B (NF-κB) activation in a luciferase-based reporter gene assay. Since several natural products inhibited NF-κB expression in THP-1 macrophages, their effect on reactive oxygen species (ROS) production and inflammasome activation was assessed, as well as their transcriptional outcome regarding ER stress. The bioactivities of several natural products are described herein for the first time. We report the anti-inflammatory potential of guaiazulene and describe 5-deoxykaempferol as a novel inhibitor of inflammasome activation. Furthermore, we describe the dual potential of 5-deoxykaempferol, berberine, guaiazulene, luteolin-4’-O-glucoside, myricetin, quercetagetin and sennoside B to modulate inflammatory signaling ER stress. Our results show that natural products are promising molecules for the discovery and pharmaceutical development of chemical entities able to modulate the inflammatory response, as well as proteostasis and the UPR.

内质网（ER）是维持细胞蛋白质稳态的决定因素。当内质网应激未解决时，该细胞器会激活未折叠蛋白反应（UPR）。已知持续的 UPR 激活发生在炎症过程中，因此 ER 是治疗炎症的潜在分子靶点。这项工作描述了由内部天然产物库调节的炎症/UPR相关分子机制，旨在为开发作用于内质网以对抗炎症相关慢性疾病的新选择性药物铺平道路。从 134 种天然存在的化合物（主要存在于药用植物中）开始，在基于荧光素酶的报告基因测定中筛选无毒分子对 LPS 诱导的核因子 kappa B (NF-κB) 激活的抑制能力。由于几种天然产物抑制 THP-1 巨噬细胞中 NF-κB 的表达，因此评估了它们对活性氧 (ROS) 产生和炎症小体激活的影响，以及它们与 ER 应激相关的转录结果。本文首次描述了几种天然产物的生物活性。我们报告了愈创蓝油烯的抗炎潜力，并将 5-脱氧山奈酚描述为一种新型炎症小体激活抑制剂。此外，我们描述了 5-脱氧山奈酚、小檗碱、愈创蓝油烯、木犀草素-4'- O-葡萄糖苷、杨梅素、槲皮素和番泻苷 B 调节炎症信号内质网应激的双重潜力。我们的结果表明，天然产物是能够调节炎症反应以及蛋白质稳态和 UPR 的化学实体的发现和药物开发的有前途的分子。