Polyunsaturated fatty acids (PUFA) are fundamental building materials for cells and play crucial function as signaling molecules. When PUFA are used as substrates for non-enzymatic or enzymatic reactions and gut microbiota metabolism, they can generate electrophilic derivatives (called Reactive Lipid Species, RLS) that promptly form adducts with nucleophilic molecules. RLS participate in several signaling pathways, including the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, which is the key mechanism in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation.

Recent studies have provided insights on the localization of enzymes that synthesise reactive oxygen or nitrogen species (ROS or RNS respectively) in plasma membrane compartments (raft/caveolae) which also harbour PUFA esters, from which free acid forms can be released by phospholipase A2 activity (PLA₂), and the complex of Nrf2 with the inhibitory protein Kelch-like ECH-associated Protein 1(Keap1). Additional investigations have indicated that dietary PUFA insertion into specific plasma membrane microdomains may alter the lipid environment and thereby influence caveolar composition and cell signaling. Given that PUFA-originated RLS attack such a complex and promote the release of active Nrf2, it cannot be excluded that all the biochemical machinery for Nrf2 activation is present in caveolae, where it triggers the Nrf2-mediated adaptive response for rescuing or maintaining cellular redox homeostasis.

Here, we specifically aimed to summarize current information with regard to the roles of dietary PUFA and RLS in Nrf2-mediated redox homeostasis, namely 1) their role as Nrf2 activators, 2) the significance of the in vivo conversion of PUFA into RLS and 3) the caveolar involvement in cell signaling for redox homeostasis.

多不饱和脂肪酸 (PUFA) 是细胞的基本构建材料，作为信号分子起着至关重要的作用。当 PUFA 用作非酶促或酶促反应和肠道微生物群代谢的底物时，它们可以产生亲电衍生物（称为反应性脂质，RLS），并迅速与亲核分子形成加合物。RLS 参与多种信号通路，包括激活核因子红细胞 2 相关因子 2 (Nrf2) 通路，这是维持氧化还原、代谢和蛋白质稳态以及调节炎症的关键机制。

最近的研究提供了关于合成活性氧或氮物种（分别为 ROS 或 RNS）的酶在质膜隔室（筏/小窝）中的定位的见解，这些隔室也含有 PUFA 酯，游离酸形式可以通过磷脂酶 A2 活性释放(PLA ₂)，以及 Nrf2 与抑制蛋白 Kelch 样 ECH 相关蛋白 1 (Keap1) 的复合物。其他研究表明，膳食 PUFA 插入特定的质膜微区可能会改变脂质环境，从而影响小窝组成和细胞信号传导。鉴于 PUFA 起源的 RLS 攻击这样一个复合体并促进活性 Nrf2 的释放，不能排除 Nrf2 激活的所有生化机制都存在于小窝中，它触发 Nrf2 介导的适应性反应，以拯救或维持细胞氧化还原体内平衡。

在这里，我们特别旨在总结有关膳食 PUFA 和 RLS 在 Nrf2 介导的氧化还原稳态中的作用的当前信息，即 1) 它们作为 Nrf2 激活剂的作用，2) PUFA在体内转化为 RLS的重要性和 3 ）细胞信号传导中的细胞膜泡参与氧化还原稳态。