细胞代谢重编程对于维持癌症干细胞（CSCs）状态至关重要。在这里，我们报告了线粒体D乳酸代谢在食管鳞状细胞癌（ESCC）发生过程中是必要的致癌事件。我们发现细胞周期依赖性激酶7（CDK7）以S127和S397位点磷酸化细胞核结合于Yes-associated protein 1（YAP），增强其转录功能，从而促进D乳酸脱氢酶（LDHD）蛋白的表达。此外，LDHD在ESCC-CSCs中富集明显，而非分化肿瘤细胞中则较低，并且高LDHD水平与ESCC患者的预后不良有联系。从机制上讲，CDK7-YAP-LDHD轴有助于ESCC-CSCs逃避D乳酸诱导的铁死亡，产生丙酮酸以满足其升高的自我更新潜能的能量需求。因此，我们得出结论，食管干细胞采用了依赖于CDK7-YAP-LDHD轴的D乳酸消除和丙酮酸积累模式，这推动了ESCC-CSCs的干细胞特征标志。合理地说，靶向代谢检查点可能作为一种有效的ESCC治疗策略。©2023年四川大学华西医院。

Reprogrammed cellular metabolism is essential for maintaining cancer stem cells (CSCs) state. Here, we report that mitochondrial D-lactate catabolism is a necessary initiating oncogenic event during tumorigenesis of esophageal squamous cell carcinoma (ESCC). We discover that cyclin-dependent kinase 7 (CDK7) phosphorylates nuclear Yes-associated protein 1 (YAP) at S127 and S397 sites and enhances its transcription function, which promotes D-lactate dehydrogenase (LDHD) protein expression. Moreover, LDHD is enriched significantly in ESCC-CSCs rather than differentiated tumor cells and high LDHD status is connected with poor prognosis in ESCC patients. Mechanistically, the CDK7-YAP-LDHD axis helps ESCC-CSCs escape from ferroptosis induced by D-lactate and generates pyruvate to satisfy energetic demands for their elevated self-renewal potential. Hence, we conclude that esophageal CSCs adopt a D-lactate elimination and pyruvate accumulation mode dependent on CDK7-YAP-LDHD axis, which drives stemness-associated hallmarks of ESCC-CSCs. Reasonably, targeting metabolic checkpoints may serve as an effective strategy for ESCC therapy.© 2023. West China Hospital, Sichuan University.