Circadian disruption predicts poor cancer prognosis, yet how circadian disruption is sensed in sleep-deficiency (SD)-enhanced tumorigenesis remains obscure. Here, we show fatty acid oxidation (FAO) as a circadian sensor relaying from clock disruption to oncogenic metabolic signal in SD-enhanced lung tumorigenesis. Both unbiased transcriptomic and metabolomic analyses reveal that FAO senses SD-induced circadian disruption, as illustrated by continuously increased palmitoyl-coenzyme A (PA-CoA) catalyzed by long-chain fatty acyl-CoA synthetase 1 (ACSL1). Mechanistically, SD-dysregulated CLOCK hypertransactivates ACSL1 to produce PA-CoA, which facilitates CLOCK-Cys194 S-palmitoylation in a ZDHHC5-dependent manner. This positive transcription-palmitoylation feedback loop prevents ubiquitin-proteasomal degradation of CLOCK, causing FAO-sensed circadian disruption to maintain SD-enhanced cancer stemness. Intriguingly, timed β-endorphin resets rhythmic Clock and Acsl1 expression to alleviate SD-enhanced tumorigenesis. Sleep quality and serum β-endorphin are negatively associated with both cancer development and CLOCK/ACSL1 expression in patients with cancer, suggesting dawn-supplemented β-endorphin as a potential chronotherapeutic strategy for SD-related cancer.

昼夜节律紊乱预示着癌症预后不佳，但如何在睡眠不足（SD）增强的肿瘤发生中感知昼夜节律紊乱仍然不清楚。在这里，我们展示了脂肪酸氧化 (FAO) 作为一种昼夜节律传感器，在 SD 增强的肺部肿瘤发生中从时钟中断传递到致癌代谢信号。无偏见的转录组学和代谢组学分析均表明，FAO 感受到了 SD 诱导的昼夜节律紊乱，如长链脂肪酰辅酶 A 合成酶 1 (ACSL1) 催化的棕榈酰辅酶 A (PA-CoA) 持续增加所示。从机制上讲，SD 失调的 CLOCK 过度激活 ACSL1 产生 PA-CoA，从而以 ZDHHC5 依赖性方式促进 CLOCK-Cys194 S-棕榈酰化。这种正转录-棕榈酰化反馈环路可防止 CLOCK 的泛素-蛋白酶体降解，从而导致 FAO 感知的昼夜节律紊乱，从而维持 SD 增强的癌症干细胞性。有趣的是，定时 β-内啡肽重置节律时钟和Acsl1表达，以减轻 SD 增强的肿瘤发生。睡眠质量和血清 β-内啡肽与癌症患者的癌症发展和 CLOCK/ACSL1 表达呈负相关，这表明补充 β-内啡肽可作为 SD 相关癌症的潜在时间治疗策略。