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<p>Tumor necrosis factor-alpha (TNF-α) plays paradoxical roles in cancer, promoting tumor survival via NF-κB activation while also inducing necroptotic cell death. Here, we identify the intracellular pH (pHᵢ) as a decisive switch that reprograms TNF-α signaling from a prosurvival inflammatory response toward tumoricidal necroptosis. In both hepatocellular and cervical carcinoma models, alkalizing the pHᵢ with bicarbonate inhibits TNF-α-mediated IκB phosphorylation and NF-κB nuclear translocation while simultaneously activating the TNF-α-driven necroptotic cascade, which is characterized by the sequential phosphorylation of RIPK1, RIPK3, and MLKL. Mechanistically, bicarbonate induces the depolarization of the mitochondrial membrane potential, reactive oxygen species (ROS) generation, and a cyclophilin D-dependent permeability transition—effects that are synergistically amplified by TNF-α. Genetic knockdown of RIPK1 or RIPK3 abrogates necroptosis, whereas the pharmacological inhibition of ROS suppresses necroptosis and concurrently restores NF-κB nuclear translocation. ROS are identified as the key mediators determining the switch between these opposing TNF-α signaling pathways. In vivo, bicarbonate and TNF-α treatment suppresses tumor growth, enhances necroptotic signaling, and inhibits NF-κB activation. Thus, our work indicates that intracellular alkalization acts as a modifiable regulator to redirect TNF-α from a toxic, proinflammatory cytokine into a potent and selective tumoricidal agent.</p><p></p>

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Alkalization of the intracellular pH reprograms TNF-α signaling from inflammatory NF-κB activation to tumoricidal RIP kinase-dependent necroptosis in cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月8日

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  • Chang Ying,
  • Di Wang,
  • Si-ying Zeng,
  • Cheng-meng Jin,
  • Min-feng Ying,
  • Xun Hu

摘要

Tumor necrosis factor-alpha (TNF-α) plays paradoxical roles in cancer, promoting tumor survival via NF-κB activation while also inducing necroptotic cell death. Here, we identify the intracellular pH (pHᵢ) as a decisive switch that reprograms TNF-α signaling from a prosurvival inflammatory response toward tumoricidal necroptosis. In both hepatocellular and cervical carcinoma models, alkalizing the pHᵢ with bicarbonate inhibits TNF-α-mediated IκB phosphorylation and NF-κB nuclear translocation while simultaneously activating the TNF-α-driven necroptotic cascade, which is characterized by the sequential phosphorylation of RIPK1, RIPK3, and MLKL. Mechanistically, bicarbonate induces the depolarization of the mitochondrial membrane potential, reactive oxygen species (ROS) generation, and a cyclophilin D-dependent permeability transition—effects that are synergistically amplified by TNF-α. Genetic knockdown of RIPK1 or RIPK3 abrogates necroptosis, whereas the pharmacological inhibition of ROS suppresses necroptosis and concurrently restores NF-κB nuclear translocation. ROS are identified as the key mediators determining the switch between these opposing TNF-α signaling pathways. In vivo, bicarbonate and TNF-α treatment suppresses tumor growth, enhances necroptotic signaling, and inhibits NF-κB activation. Thus, our work indicates that intracellular alkalization acts as a modifiable regulator to redirect TNF-α from a toxic, proinflammatory cytokine into a potent and selective tumoricidal agent.