Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes and are ubiquitously used for their anti-inflammatory properties. However, COX inhibition alone fails to explain numerous clinical outcomes of NSAID usage. Screening commonly used NSAIDs in primary human and murine myeloid cells demonstrated that NSAIDs could be differentiated by their ability to induce growth/differentiation factor 15 (GDF15), independent of COX specificity. Using genetic and pharmacologic approaches, NSAID-mediated GDF15 induction was dependent on the activation of nuclear factor erythroid 2-related factor 2 (NRF2) in myeloid cells. Sensing by Cysteine 151 of the NRF2 chaperone, Kelch-like ECH-associated protein 1 (KEAP1) was required for NSAID activation of NRF2 and subsequent anti-inflammatory effects both in vitro and in vivo. Myeloid-specific deletion of NRF2 abolished NSAID-mediated tissue protection in murine models of gout and endotoxemia. This highlights a noncanonical NRF2-dependent mechanism of action for the anti-inflammatory activity of a subset of commonly used NSAIDs.

非甾体类抗炎药 (NSAID) 可抑制环氧合酶 (COX)，并因其抗炎特性而被广泛使用。然而，单独使用 COX 抑制并不能解释 NSAID 使用的众多临床结果。在原代人和小鼠骨髓细胞中筛选常用的非甾体抗炎药表明，非甾体抗炎药可以通过它们诱导生长/分化因子 15 (GDF15) 的能力来区分，而与 COX 特异性无关。使用遗传学和药理学方法，NSAID 介导的 GDF15 诱导依赖于骨髓细胞中核因子红细胞 2 相关因子 2 (NRF2) 的激活。通过 NRF2 伴侣的半胱氨酸 151 感应，Kelch 样 ECH 相关蛋白 1 (KEAP1) 是 NSAID 激活 NRF2 和随后的体外抗炎作用所必需的和体内。NRF2 的骨髓特异性缺失消除了痛风和内毒素血症小鼠模型中 NSAID 介导的组织保护作用。这突出了常用 NSAID 子集的抗炎活性的非规范 NRF2 依赖性作用机制。