Altered human aldo-keto reductase family 1 member C3 (AKR1C3) expression has been associated with poor prognosis in diverse cancers, ferroptosis resistance, and metabolic diseases. Despite its clinical significance, the endogenous biochemical roles of AKR1C3 remain incompletely defined. Using untargeted metabolomics, we identified a major transformation mediated by AKR1C3, in which a spermine oxidation product “sperminal” is reduced to “sperminol.” Sperminal causes DNA damage and activates the DNA double-strand break response, whereas sperminol induces autophagy in vitro. AKR1C3 also pulls down acyl-pyrones and pyrone-211 inhibits AKR1C3 activity. Through G protein-coupled receptor ligand screening, we determined that pyrone-211 is also a potent agonist of the semi-orphan receptor GPR84. Strikingly, mammalian fatty acid synthase produces acyl-pyrones in vitro, and this production is modulated by NADPH. Taken together, our studies support a regulatory role of AKR1C3 in an expanded polyamine pathway and a model linking fatty acid synthesis and NADPH levels to GPR84 signaling.

人类醛酮还原酶家族 1 成员 C3 (AKR1C3) 表达的改变与多种癌症、铁死亡抵抗和代谢疾病的不良预后相关。尽管具有临床意义，但 AKR1C3 的内源生化作用仍未完全确定。利用非靶向代谢组学，我们发现了 AKR1C3 介导的重大转化，其中精胺氧化产物“精胺”被还原为“精胺醇”。精精会引起 DNA 损伤并激活 DNA 双链断裂反应，而精胺醇会在体外诱导自噬。 AKR1C3 还会降低酰基吡喃酮，pyrone-211 会抑制 AKR1C3 活性。通过G蛋白偶联受体配体筛选，我们确定pyrone-211也是半孤儿受体GPR84的有效激动剂。引人注目的是，哺乳动物脂肪酸合酶在体外产生酰基吡喃酮，并且这种产生受到 NADPH 的调节。总而言之，我们的研究支持 AKR1C3 在扩展的多胺途径中的调节作用以及将脂肪酸合成和 NADPH 水平与 GPR84 信号传导联系起来的模型。