越来越多的证据表明，细胞竞争是多细胞生物中重要的选择和质量控制机制，与肿瘤的发生和发展有关。然而，细胞竞争与肿瘤耐药性之间的关联机制仍然不明确。在我们的研究中，基于构建的乐维替尼耐药性肝细胞癌（HCC）细胞通过重新编程能量代谢，表现出比敏感细胞明显的竞争性生长优势。从机制上讲，乐伐替尼耐药 HCC 细胞中 BCL2 相互作用蛋白 3 (BNIP3) 介导的线粒体自噬过度激活，通过调节 AMP 激活蛋白激酶 (AMPK) -烯醇化酶 2 (ENO2)，将能量产生从线粒体氧化磷酸化转变为糖酵解，从而促进糖酵解通量信号传导，永久保持乐伐替尼耐药 HCC 细胞相对于敏感 HCC 细胞的竞争优势。值得注意的是，BNIP3 抑制显着提高了乐伐替尼在 HCC 中的抗肿瘤功效。我们的研究结果强调了 BNIP3-AMPK-ENO2 信号在通过调节能量代谢重编程维持乐维替尼耐药性 HCC 细胞的竞争结果方面发挥着至关重要的作用；同时，这项工作认识到 BNIP3 是克服 HCC 耐药性的有希望的靶标。© 2024。作者。

An increasing evidence supports that cell competition, a vital selection and quality control mechanism in multicellular organisms, is involved in tumorigenesis and development; however, the mechanistic contributions to the association between cell competition and tumor drug resistance remain ill-defined. In our study, based on a contructed lenvitinib-resistant hepatocellular carcinoma (HCC) cells display obvious competitive growth dominance over sensitive cells through reprogramming energy metabolism. Mechanistically, the hyperactivation of BCL2 interacting protein3 (BNIP3) -mediated mitophagy in lenvatinib-resistant HCC cells promotes glycolytic flux via shifting energy production from mitochondrial oxidative phosphorylation to glycolysis, by regulating AMP-activated protein kinase (AMPK) -enolase 2 (ENO2) signaling, which perpetually maintaining lenvatinib-resistant HCC cells' competitive advantage over sensitive HCC cells. Of note, BNIP3 inhibition significantly sensitized the anti-tumor efficacy of lenvatinib in HCC. Our findings emphasize a vital role for BNIP3-AMPK-ENO2 signaling in maintaining the competitive outcome of lenvitinib-resistant HCC cells via regulating energy metabolism reprogramming; meanwhile, this work recognizes BNIP3 as a promising target to overcome HCC drug resistance.© 2024. The Author(s).