Tang Jie, Liu Wenqiang, Li Zihan, Shen Can, Zhang Longbiao, Wang Cheng, Wang Fengshuo, Zai Zhuoyan, Qian Xuewen, Hu Weirong, Zhang Xiaoyue, Peng Xiaoqing, Xu Yayun, Chen Feihu
School of Pharmacy, Anhui Medical University, Hefei, China.
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, China.
FASEB J. 2025 Jan 15;39(1):e70298. doi: 10.1096/fj.202402134RR.
The activation of acid-sensing ion channel 1a (ASIC1a) in response to extracellular acidification leads to an increase in extracellular calcium influx, thereby exacerbating the degeneration of articular chondrocytes in rheumatoid arthritis (RA). It has been suggested that the inhibition of extracellular calcium influx could potentially impede chondrocyte ferroptosis. The cystine transporter, solute carrier family 7 member 11 (SLC7A11), is recognized as a key regulator of ferroptosis. Recent studies suggest that the tumor suppressor gene p53 facilitates the induction of ferroptosis by suppressing the upregulation of SLC7A11. This process is mediated by the nuclear factor erythroid 2-related factor 2 (NRF2), a key transcription factor integral to the maintenance of cellular redox homeostasis and the regulation of inflammatory responses. This study aims to investigate the role of ASIC1a in the ferroptosis of RA chondrocytes and to determine the involvement of the p53/NRF2/SLC7A11 pathway in its underlying mechanism. In vitro experiments revealed that acidosis induces ferroptosis and reduces the expression of NRF2 and SLC7A11 in chondrocytes. Moreover, acidification significantly increased p53 protein levels in chondrocytes. Pifithrin-α (PFN-α), a p53 inhibitor, mitigated acidosis-induced ferroptosis and restored the diminished expression of NRF2 and SLC7A11. Furthermore, PcTx-1, an ASIC1a inhibitor, inhibited acidification-induced ferroptosis, enhanced the protein levels of SLC7A11 and NRF2, and reduced p53 expression. In vivo experiments demonstrated that the ASIC1a-specific inhibitor PcTx-1 ameliorated histopathological characteristics of ankle joints in collagen-induced arthritis (CIA) mice, decreased p53 expression, and enhanced NRF2 and SLC7A11 expression in chondrocytes. These findings suggest that ASIC1a inhibition may mitigate acidification-induced ferroptosis in articular chondrocytes in RA, potentially via the p53/NRF2/SLC7A11 pathway.
酸敏感离子通道1a（ASIC1a）对细胞外酸化的激活会导致细胞外钙内流增加，从而加剧类风湿关节炎（RA）中关节软骨细胞的退变。有人提出，抑制细胞外钙内流可能会阻碍软骨细胞铁死亡。胱氨酸转运体溶质载体家族7成员11（SLC7A11）被认为是铁死亡的关键调节因子。最近的研究表明，肿瘤抑制基因p53通过抑制SLC7A11的上调来促进铁死亡的诱导。这一过程由核因子红细胞2相关因子2（NRF2）介导，NRF2是维持细胞氧化还原稳态和调节炎症反应所必需的关键转录因子。本研究旨在探讨ASIC1a在RA软骨细胞铁死亡中的作用，并确定p53/NRF2/SLC7A11通路在其潜在机制中的参与情况。体外实验表明，酸中毒可诱导软骨细胞铁死亡，并降低NRF2和SLC7A11的表达。此外，酸化显著增加了软骨细胞中p53蛋白水平。p53抑制剂匹莫苯丹（PFN-α）减轻了酸中毒诱导的铁死亡，并恢复了NRF2和SLC7A11表达的降低。此外，ASIC1a抑制剂芋螺毒素PcTx-1抑制了酸化诱导的铁死亡，提高了SLC7A11和NRF2的蛋白水平，并降低了p53表达。体内实验表明，ASIC1a特异性抑制剂PcTx-1改善了胶原诱导性关节炎（CIA）小鼠踝关节的组织病理学特征，降低了p53表达，并增强了软骨细胞中NRF2和SLC7A11的表达。这些发现表明，抑制ASIC1a可能通过p53/NRF2/SLC7A11通路减轻RA中关节软骨细胞酸化诱导的铁死亡。
