炎症和代谢重编程是癌症的标志。炎症如何调节癌症代谢目前知之甚少。我们的研究发现，3-羟基-3-甲基戊二酰辅酶A裂解酶（HMGCL）是一种催化亮氨酸分解并促进酮体合成的酶，在肺癌中下调。HMGCL的下调与更大的肿瘤大小和较短的总生存时间有关。在功能研究中，HMGCL的过表达增加了β-羟基丁酸（β-HB）的含量并抑制了肺癌细胞的肿瘤原性，而HMGCL的删除则促进了KP（KrasG12D；P53f/f）小鼠的新生癌症形成。在机制上，肿瘤坏死因子α（TNFα）处理降低了HMGCL蛋白的水平，IKKβ与HMGCL相互作用并在Ser258处磷酸化HMGCL，从而使HMGCL不稳定。此外，我们还发现NEDD4是HMGCL的E3连接酶，并促进了其降解。此外，将Ser258突变为丙氨酸可以抑制NEDD4对HMGCL的泛素化，并且比野生型HMGCL更有效地抑制肺癌细胞的无定形生长。总之，本研究证明了TNFα介导的炎症和癌症代谢之间的联系。©作者。

Inflammation and metabolic reprogramming are hallmarks of cancer. How inflammation regulates cancer metabolism remains poorly understood. In this study, we found that 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL), the enzyme that catalyzes the catabolism of leucine and promotes the synthesis of ketone bodies, was downregulated in lung cancer. Downregulation of HMGCL was associated with a larger tumor size and a shorter overall survival time. In a functional study, overexpression of HMGCL increased the content of β-hydroxybutyrate (β-HB) and inhibited the tumorigenicity of lung cancer cells, and deletion of HMGCL promoted de novo tumorigenesis in KP (KrasG12D;P53f/f) mice. Mechanistically, tumor necrosis factor α (TNFα) treatment decreased the HMGCL protein level, and IKKβ interacted with HMGCL and phosphorylated it at Ser258, which destabilized HMGCL. Moreover, NEDD4 was identified as the E3 ligase for HMGCL and promoted its degradation. In addition, mutation of Ser258 to alanine inhibited the ubiquitination of HMGCL by NEDD4 and thus inhibited the anchorage-independent growth of lung cancer cells more efficiently than did wild-type HMGCL. In summary, this study demonstrated a link between TNFα-mediated inflammation and cancer metabolism.© The author(s).