NFAT5 exacerbates β-cell ferroptosis by suppressing the transcription of PRDX2 in obese type 2 diabetes mellitus.

Summary

In obese T2D mice and β-cell models, NFAT5 expression and nuclear translocation increase under glucolipotoxicity, driving β-cell ferroptosis by repressing PRDX2 transcription. Genetic inhibition of NFAT5 in β cells reduces ferroptosis, enhances insulin secretion, and improves glucose tolerance in vivo.

Key Findings

• Glucolipotoxicity increases NFAT5 expression and nuclear translocation in MIN6 cells and obese T2D mouse islets.
• NFAT5 binds the PRDX2 promoter, repressing its transcription and promoting β-cell ferroptosis and insulin secretory failure.
• β-cell–specific NFAT5 knockdown (AAV8-RIP2-miR30-shNFAT5) reduces ferroptosis, increases insulin secretion, and improves glucose tolerance in obese T2D mice.

Clinical Implications

Suggests that inhibiting NFAT5 or boosting PRDX2/antioxidant defenses, or employing ferroptosis modulators, may preserve β-cell function in T2D; supports biomarker development around ferroptosis signatures.

Limitations

• Translation to human β cells and clinical T2D remains to be demonstrated.
• Potential off-target or compensatory effects with AAV-based gene modulation were not fully explored.

Future Directions

Evaluate NFAT5 inhibitors or PRDX2-enhancing approaches in human islets and diabetic models; test ferroptosis-targeted therapies alongside standard T2D treatments.