对于肺癌脑转移（BM）患者，对能够有效穿过血脑屏障的罕见化疗药物培美曲塞（PEM）的耐药性限制了治疗效果。最近发现醛酮还原酶家族1B10（AKR1B10）在肺癌脑转移中升高，然而AKR1B10与获得性PEM耐药的联系尚不清楚。我们通过体外和体内PC9肺腺癌细胞BM模型以及具有或没有AKR1B10干预的BM细胞，评估了PEM对药物敏感性。通过色谱质谱（GC-MS）代谢组学鉴定了AKR1B10致使BM代谢重编程。通过RNA测序和进一步的分子生物学实验方法揭示了AKR1B10通过改变代谢途径介导PEM化疗耐药的机制。肺癌脑转移亚群细胞(PC9-BrM3)对PEM表现出显著耐药性，在体外和体内抑制AKR1B10会增加PC9-BrM3對PEM的敏感性。代谢谱揭示了AKR1B10显著促进戊糖代谢，以乳酸的过度产生为特征。由AKR1B10调控的糖酵解对PEM的耐药性至关重要。机制上，AKR1B10通过调节乳酸脱氢酶（LDHA）的表达促进糖酵解，并通过增加乳酸作为前体来刺激组蛋白乳酸化（H4K12la），激活CCNB1的转录，加速DNA复制和细胞周期。我们的发现表明，在肺癌BM中，AKR1B10/糖酵解/H4K12la/CCNB1促进了PEM的获得性化疗耐药性，为在治疗患有BM的肺癌患者中增加PEM响应提供了新策略。© 2023. BioMed Central Ltd.,位于Springer Nature旗下。

Resistance to pemetrexed (PEM), a rare chemotherapeutic agent that can efficiently cross the blood-brain barrier, limits the therapeutic efficacy for patients with lung cancer brain metastasis (BM). Aldo-keto reductase family 1 B10 (AKR1B10) was recently found to be elevated in lung cancer BM. The link between AKR1B10 and BM-acquired PEM is unknown.PEM drug-sensitivity was assessed in the preclinical BM model of PC9 lung adenocarcinoma cells and the BM cells with or without AKR1B10 interference in vitro and in vivo. Metabolic reprogramming of BM attributed to AKR1B10 was identified by chromatography-mass spectrometry (GC-MS) metabolomics, and the mechanism of how AKR1B10 mediates PEM chemoresistance via a way of modified metabolism was revealed by RNA sequencing as well as further molecular biology experimental approaches.The lung cancer brain metastatic subpopulation cells (PC9-BrM3) exhibited significant resistance to PEM and silencing AKR1B10 in PC9-BrM3 increased the PEM sensitivity in vitro and in vivo. Metabolic profiling revealed that AKR1B10 prominently facilitated the Warburg metabolism characterized by the overproduction of lactate. Glycolysis regulated by AKR1B10 is vital for the resistance to PEM. In mechanism, AKR1B10 promoted glycolysis by regulating the expression of lactate dehydrogenase (LDHA) and the increased lactate, acts as a precursor that stimulates histone lactylation (H4K12la), activated the transcription of CCNB1 and accelerated the DNA replication and cell cycle.Our finding demonstrates that AKR1B10/glycolysis/H4K12la/CCNB1 promotes acquired PEM chemoresistance in lung cancer BM, providing novel strategies to sensitize PEM response in the treatment of lung cancer patients suffering from BM.© 2023. BioMed Central Ltd., part of Springer Nature.