<scp>ELAVL1</scp> Promotes Schwann Cell Oxidative Stress and Ferroptosis in Diabetic Neuropathy via <scp>ACSL4 mRNA</scp> Stabilization

ELAVL1 is known to regulate mRNA stability in various diseases, but its role in ferroptosis and Schwann cell dysfunction in diabetic peripheral neuropathy (DPN) has not been previously explored. This study investigates the mechanistic role of ELAVL1 in Schwann cell ferroptosis and explores the therapeutic potential of bone marrow-derived mesenchymal stem cells (BMSCs) in alleviating DPN. We used a streptozotocin (STZ)-induced diabetic mouse model and high-glucose-treated Schwann cells to study DPN-associated neuropathy, oxidative stress, and ferroptosis. ELAVL1 expression was analyzed in DPN patients and diabetic mice. A Schwann cell-specific ELAVL1 knockout (ELAVL1-KO) mouse model was developed to assess its impact on nerve function and oxidative stress. Mechanistic studies examined ELAVL1 interaction with ACSL4 mRNA in ferroptosis. Finally, BMSCs were administered at different doses to evaluate their effects on the ELAVL1/ACSL4 pathway. We found that ELAVL1 was significantly upregulated in the sciatic nerves of DPN patients and STZ-induced DPN mice. ELAVL1 co-localized with Schwann cells and contributed to myelin damage, oxidative stress, and ferroptosis. Knockdown of ELAVL1 in Schwann cells improved sciatic nerve conduction, reduced oxidative stress, and restored myelin integrity in DPN mice. Mechanistically, ELAVL1 promoted ferroptosis by binding to the 3'-UTR of ACSL4 mRNA, thereby stabilizing ACSL4 expression. Notably, BMSC therapy downregulated ELAVL1 and ACSL4 expression in a dose-dependent manner, reducing oxidative stress, iron accumulation, and ferroptosis. In conclusion, ELAVL1 promotes Schwann cell ferroptosis in DPN via ACSL4 mRNA stabilization. Furthermore, BMSC therapy reduces ferroptosis by modulating the ELAVL1/ACSL4 axis, offering a promising approach for DPN treatment.