Inhibition of ASIC1a reduces ferroptosis in rheumatoid arthritis articular chondrocytes via the p53/NRF2/SLC7A11 pathway

FASEB J. 2025 Jan 15;39(1):e70298. doi: 10.1096/fj.202402134RR.

Abstract

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.

Keywords: acid‐sensing ion channel 1a; chondrocytes; ferroptosis; p53/NRF2/SLC7A11 pathway; rheumatoid arthritis.

MeSH terms

  • Acid Sensing Ion Channels* / genetics
  • Acid Sensing Ion Channels* / metabolism
  • Amino Acid Transport System y+* / genetics
  • Amino Acid Transport System y+* / metabolism
  • Animals
  • Arthritis, Experimental / metabolism
  • Arthritis, Experimental / pathology
  • Arthritis, Rheumatoid* / metabolism
  • Arthritis, Rheumatoid* / pathology
  • Cartilage, Articular / metabolism
  • Cartilage, Articular / pathology
  • Cells, Cultured
  • Chondrocytes* / metabolism
  • Chondrocytes* / pathology
  • Ferroptosis* / physiology
  • Humans
  • Male
  • Mice
  • NF-E2-Related Factor 2* / genetics
  • NF-E2-Related Factor 2* / metabolism
  • Signal Transduction
  • Tumor Suppressor Protein p53* / metabolism

Substances

  • Acid Sensing Ion Channels
  • Tumor Suppressor Protein p53
  • NF-E2-Related Factor 2
  • Amino Acid Transport System y+
  • Slc7a11 protein, mouse
  • ASIC1 protein, human
  • Nfe2l2 protein, mouse
  • SLC7A11 protein, human
  • ASIC1 protein, mouse