Fatty acid esters of hydroxy fatty acids (FAHFAs) represent a complex lipid class that contains both signaling mediators and structural components of lipid biofilms in humans. The majority of endogenous FAHFA share a common chemical architecture, characterized by an estolide bond that links the hydroxy fatty acid (HFA) backbone and the fatty acid (FA). Two structurally and functionally distinct FAHFA superfamilies are recognized based on the position of the estolide bond: omega-FAHFAs and in-chain branched FAHFAs. The existing variety of possible HFAs and FAs combined with the position of the estolide bond generates a vast quantity of unique structures identified in FAHFA families.

In this review, we discuss the anti-diabetic and anti-inflammatory effects of branched FAHFAs and the role of omega-FAHFA-derived lipids as surfactants in the tear film lipid layer and dry eye disease. To emphasize potential pharmacological targets, we recapitulate the biosynthesis of the HFA backbone within the superfamilies together with the degradation pathways and the FAHFA regioisomer distribution in human and mouse adipose tissue. We propose a theoretical involvement of cytochrome P450 enzymes in the generation and degradation of saturated HFA backbones and present an overview of small-molecule inhibitors used in FAHFA research.

The FAHFA lipid class is huge and largely unexplored. Besides the unknown biological effects of individual FAHFAs, also the enigmatic enzymatic machinery behind their synthesis could provide new therapeutic approaches for inflammatory metabolic or eye diseases. Therefore, understanding the mechanisms of (FA)HFA synthesis at the molecular level should be the next step in FAHFA research.

羟基脂肪酸的脂肪酸酯 (FAHFA) 代表一种复杂的脂质类别，其中包含信号传导介质和人体脂质生物膜的结构成分。大多数内源性 FAHFA 具有共同的化学结构，其特征是连接羟基脂肪酸 (HFA) 主链和脂肪酸 (FA) 的酯键。基于 estolide 键的位置识别出两个结构和功能不同的 FAHFA 超家族：omega-FAHFA 和链内支链 FAHFA。现有的各种可能的 HFA 和 FA 与 estolide 键的位置相结合，产生了大量在 FAHFA 家族中鉴定的独特结构。

在这篇综述中，我们讨论了支链 FAHFA 的抗糖尿病和抗炎作用，以及 omega-FAHFA 衍生的脂质作为表面活性剂在泪膜脂质层和干眼症中的作用。为了强调潜在的药理靶点，我们概括了超家族中 HFA 骨架的生物合成以及降解途径和 FAHFA 区域异构体在人和小鼠脂肪组织中的分布。我们提出细胞色素 P450 酶在理论上参与饱和 HFA 骨架的生成和降解，并概述了 FAHFA 研究中使用的小分子抑制剂。

FAHFA 脂质类是巨大的并且在很大程度上未被探索。除了单个 FAHFAs 的未知生物学效应外，它们合成背后的神秘酶机制也可以为炎症性代谢或眼部疾病提供新的治疗方法。因此，从分子水平了解（FA）HFA合成的机制应该是FAHFA研究的下一步。