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<p>This study unveils PKM2 as a master metabolic coordinator in triple-negative breast cancer (TNBC), governing the glycolysis-lipolysis balance through the&#xa0;AMPK/KLF4/ACADVL axis. We demonstrate stage-specific PKM2 upregulation in TNBC, with CRISPR/Cas9 knockout inducing&#xa0;dual metabolic reprogramming—suppressed glycolysis and activated lipid catabolism. Mechanistically, PKM2 ablation triggers AMPK-dependent nuclear translocation of KLF4, which directly activates ACADVL (mitochondrial β-oxidation rate-limiting enzyme), explaining lipid droplet depletion. Therapeutically,&#xa0;synergistic lethality&#xa0;emerges from combining PKM2 knockout with ACADVL inhibition, suggesting metabolic redundancy disruption strategies. Unlike PKM2-SCAP-mediated lipogenesis reported elsewhere, our work establishes a&#xa0;KLF4-driven lipid catabolic pathway&#xa0;specific to TNBC. Crucially, this AMPK/KLF4/ACADVL network operates independently of BRCA status, proposing targeted therapy for chemoresistant non-BRCA mutant TNBC. Our findings redefine TNBC metabolic plasticity through transcriptional-metabolic crosstalk, offering combinatorial therapeutic paradigms against metabolic adaptation.</p>

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PKM2 knockout facilitates the activation of the AMPK/KLF4/ACADVL pathway, leading to increased oxidative degradation of fatty acids in TNBC

  • 期刊论文

  • 发表日期：

    2025年3月12日

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  • Linghan Zhang,
  • Li Cheng,
  • Yingchao Ma,
  • Junlin Li,
  • Yue Zhong,
  • Xiuzhi Zhu,
  • XiaoMin Leng,
  • Fuhua Xie

摘要

This study unveils PKM2 as a master metabolic coordinator in triple-negative breast cancer (TNBC), governing the glycolysis-lipolysis balance through the AMPK/KLF4/ACADVL axis. We demonstrate stage-specific PKM2 upregulation in TNBC, with CRISPR/Cas9 knockout inducing dual metabolic reprogramming—suppressed glycolysis and activated lipid catabolism. Mechanistically, PKM2 ablation triggers AMPK-dependent nuclear translocation of KLF4, which directly activates ACADVL (mitochondrial β-oxidation rate-limiting enzyme), explaining lipid droplet depletion. Therapeutically, synergistic lethality emerges from combining PKM2 knockout with ACADVL inhibition, suggesting metabolic redundancy disruption strategies. Unlike PKM2-SCAP-mediated lipogenesis reported elsewhere, our work establishes a KLF4-driven lipid catabolic pathway specific to TNBC. Crucially, this AMPK/KLF4/ACADVL network operates independently of BRCA status, proposing targeted therapy for chemoresistant non-BRCA mutant TNBC. Our findings redefine TNBC metabolic plasticity through transcriptional-metabolic crosstalk, offering combinatorial therapeutic paradigms against metabolic adaptation.