顺铂（CPT）是肝细胞癌（HCC）的标准治疗之一。然而，由于药物耐药性，其作为单药治疗的使用受到限制，并且其潜在机制仍不清楚。为了解决这个问题，我们尝试使用卡那列食库（CANA），一种临床用于糖尿病的药物，来降低对CPT的化疗耐药性，结果显示CANA可以强力抑制细胞增殖和迁移，独立于原始靶点SGLT2。从机制上讲，CANA通过靶向PKM2在HCC中降低有氧糖酵解。被下调的PKM2直接与转录因子c-Myc在细胞质中形成复合物，上调了磷酸化的c-Myc Thr58水平，促进了c-Myc的泛素化和降解。降低的c-Myc减少了谷氨酸代谢的关键酶GLS1的表达，导致谷氨酸利用受损。最后，细胞内谷氨酸饥饿诱导了铁死亡，并使HCC对CPT产生敏感性。总之，我们的研究显示CANA通过对糖酵解和谷氨酸代谢的双重影响诱导了铁死亡，使HCC对CPT重新敏感。这是增加化疗敏感性的新机制，可能为HCC提供兼容的化疗药物。© 2023 版权归Elsevier Inc.所有。

Cisplatin (CPT) is one of the standard treatments for hepatocellular carcinoma (HCC). However, its use is limits as a monotherapy due to drug resistance, and the underlying mechanism remains unclear. To solve this problem, we tried using canagliflozin (CANA), a clinical drug for diabetes, to reduce chemoresistance to CPT, and the result showed that CANA could vigorously inhibit cell proliferation and migration independent of the original target SGLT2. Mechanistically, CANA reduced aerobic glycolysis in HCC by targeting PKM2. The downregulated PKM2 directly bound to the transcription factor c-Myc in the cytoplasm to form a complex, which upregulated the level of phosphorylated c-Myc Thr58 and promoted the ubiquitination and degradation of c-Myc. Decreased c-Myc reduced the expression of GLS1, a key enzyme in glutamine metabolism, leading to impaired glutamine utilization. Finally, intracellular glutamine starvation induced ferroptosis and sensitized HCC to CPT. In conclusion, our study showed that CANA re-sensitized HCC to CPT by inducing ferroptosis through dual effects on glycolysis and glutamine metabolism. This is a novel mechanism to increase chemosensitivity, which may provide compatible chemotherapy drugs for HCC.Copyright © 2023. Published by Elsevier Inc.