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<p>Dysregulated chondrocyte death contributes substantially to cartilage destruction in rheumatoid arthritis (RA), yet the underlying mechanisms remain incompletely understood. Here, we identify the calcium-activated potassium channel KCa3.1 as a critical mediator of chondrocyte ferroptosis and cartilage destruction in RA. We demonstrate that both genetic ablation and pharmacological inhibition of KCa3.1 alleviate lipid peroxidation, pathological mitochondrial hyperfusion and ROS accumulation, thereby inhibiting iron deposition, ultimately protecting against chondrocyte ferroptosis and cartilage destruction. In addition, inhibiting mitochondrial fusion can suppress KCa3.1-mediated-ferroptosis in chondrocytes. Mechanistically, we establish that the transcription factor FOSL1 directly binds to the KCa3.1 promoter, upregulating its expression and triggering calcium overload, pathological mitochondrial hyperfusion and ferroptotic cell death. Crucially, FOSL1 gene silencing and pharmacological inhibition can down-regulate the pathological high expression of KCa3.1, restore mitochondrial homeostasis, and reduces ferroptosis, alleviate disease progression and cartilage damage. Collectively, our findings unveil the FOSL1-KCa3.1 axis as a promising target for the treatment of RA and other ferroptosis-related pathologies.</p>

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Targeting FOSL1-KCa3.1 inhibits ferroptosis and cartilage destruction by suppressing mitochondrial hyperfusion

  • 期刊论文

  • 发表日期：

    2026年8月4日

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  • Ren-peng Zhou,
  • Shu-fang Li,
  • Ke Wang,
  • Xing-yu Liu,
  • Hao-yu Liu,
  • Peng Yu,
  • Yu-fan Zhang,
  • Wei-rong Hu,
  • Yu-cai Xu,
  • Jie Ding,
  • Cheng Sun,
  • Ying-jie Zhao,
  • Feng Yao,
  • Wei Wei,
  • Chao Lu,
  • Wei Hu

摘要

Dysregulated chondrocyte death contributes substantially to cartilage destruction in rheumatoid arthritis (RA), yet the underlying mechanisms remain incompletely understood. Here, we identify the calcium-activated potassium channel KCa3.1 as a critical mediator of chondrocyte ferroptosis and cartilage destruction in RA. We demonstrate that both genetic ablation and pharmacological inhibition of KCa3.1 alleviate lipid peroxidation, pathological mitochondrial hyperfusion and ROS accumulation, thereby inhibiting iron deposition, ultimately protecting against chondrocyte ferroptosis and cartilage destruction. In addition, inhibiting mitochondrial fusion can suppress KCa3.1-mediated-ferroptosis in chondrocytes. Mechanistically, we establish that the transcription factor FOSL1 directly binds to the KCa3.1 promoter, upregulating its expression and triggering calcium overload, pathological mitochondrial hyperfusion and ferroptotic cell death. Crucially, FOSL1 gene silencing and pharmacological inhibition can down-regulate the pathological high expression of KCa3.1, restore mitochondrial homeostasis, and reduces ferroptosis, alleviate disease progression and cartilage damage. Collectively, our findings unveil the FOSL1-KCa3.1 axis as a promising target for the treatment of RA and other ferroptosis-related pathologies.