Competitive binding of EGR1 to MDM2 causes P53 to promote high glucose-induced impairment of Schwann cell function.

Background: Diabetic neuropathic pain (DNP) is a common chronic complication of diabetes mellitus (DM). Schwann cells (SCs) dysfunction plays an important role in the pathogenesis of DNP. Early growth response protein 1 (EGR1) is related to apoptosis and immune regulation and plays important roles in neuropathic pain. However, its exact role in DNP-induced SCs injury is still unclear. Methods: A DNP mouse model was established using a high-fat diet combined with STZ, and a high glucose (HG)-induced RSC96 cell model was used for the experimental studies. The metabolic status of the mice was assessed by fasting blood glucose (FBG) levels. Pathological damage to the sciatic nerve was detected by HE staining. Pain sensitivity was comprehensively evaluated by the von Frey test and hot plate test. Cell viability was determined by a CCK-8 assay, and apoptosis was detected by TUNEL staining. Western blotting, immunohistochemistry, immunofluorescence, and ELISA were used to detect the expression of related proteins. Results: EGR1 was highly expressed in DNP mice and HG-induced RSC96 cells. Knockdown of EGR1 alleviated the symptoms of DNP mice, including a reduction in FBG levels, an increase in the tactile response threshold, a reduction in thermal response delay, and alleviation of sciatic nerve injury. In addition, EGR1 knockdown inhibited the apoptosis of SCs and inflammatory responses. In terms of molecular mechanisms, EGR1 competitively binds to MDM2 to inhibit MDM2-mediated P53 ubiquitination and increase P53 expression, thereby promoting HG-induced SC injury, whereas inhibition of MDM2 reverses the protective effect of EGR1 knockdown on SCs. Conclusion: EGR1 inhibits MDM2-mediated P53 ubiquitination and degradation by competitively binding to MDM2, resulting in the upregulation of P53 expression, thereby promoting HG-induced SC function injury and inflammatory responses and aggravating DNP. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10616-026-00935-7.