NR4A3 alleviates diabetic neuropathy via GLS2-mediated mitochondrial repair and Schwann cell differentiation

Diabetic peripheral neuropathy (DPN) is a prevalent complication characterized by Schwann cell dysfunction. The role of the nuclear receptor subfamily 4 group member 3 (NR4A3) in DPN remains unclear. We found that NR4A3 expression is upregulated in the sciatic nerves of streptozotocin (STZ)-induced DPN mice. Overexpression of NR4A3 via AAV9-Mpz-NR4A3 lumbar intrathecal injection improved motor and sensory nerve function and mitigated sciatic nerve pathology. NR4A3 overexpression also reduced oxidative stress and enhanced mitochondrial function. In the high glucose (HG)-induced Schwann cell injury model, NR4A3 overexpression inhibited apoptosis, mitochondrial dysfunction, and dedifferentiation. Integrated ChIP-seq and mRNA-seq profiling identified glutaminase 2 (GLS2) as a direct transcriptional target of NR4A3. NR4A3 binds to the GLS2 promoter and promotes its transcriptional activation, and suppression of GLS2 abrogates the functional protection conferred by NR4A3 in Schwann cells. Together, NR4A3 represents a promising therapeutic target for DPN.