ALOX15-Mediated Neuron Ferroptosis Was Involved in Diabetic Peripheral Neuropathic Pain.

Background: Diabetic peripheral neuropathic pain (DPNP) is one of the most common complications in diabetic patients. Current treatment strategies primarily focus on blood glucose control and pain relief, but they often yield limited effects. Ferroptosis, a regulated form of cell death driven by lipid peroxidation and iron imbalance, plays a crucial role in various diseases, including neuropathic pain.

Methods: In this study, we employed a combined bioinformatics and machine learning approach to identify genes most strongly associated with DPNP and ferroptosis. Subsequently, we established a DPNP mouse model via streptozotocin (STZ) injection and a high-glucose-induced SH-SY5Y cell injury model. ALOX15 was knocked down in the in vitro model using siRNA transfection.

Results: Bioinformatics analysis identified ALOX15 as a hub gene linking DPNP and ferroptosis. In both in vivo and in vitro DPNP models, ALOX15 expression was significantly upregulated and correlated with ferroptosis biomarkers. Knockdown of ALOX15 in the cellular model mitigated high-glucose-induced ferroptosis, reduced lipid peroxidation and free iron ion accumulation, and restored cell viability.

Conclusion: In conclusion, ALOX15 contributes to the onset and progression of DPNP by promoting ferroptosis, and its knockdown effectively suppresses ferroptosis, providing a novel target and strategy for DPNP treatment.