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

Diabetic peripheral neuropathic pain (DPNP) is a prevalent complication among diabetic patients. Recent studies have confirmed that ferroptosis, an iron-dependent cell death driven by lipid peroxidation, plays a key role in DPNP development. However, biomarkers related to ferroptosis in DPNP remain undiscovered. Core genes related to DPNP were identified using bioinformatics. By assessing the mechanical paw withdrawal threshold (PWT) and thermal paw withdrawal latency (PWL), a mouse model of DPNP was established, along with a high-glucose-stimulated SH-SY5Y cell model. The combination of these two models allows for an in-depth investigation of the molecular biological mechanisms underlying DPNP. The viability and ferroptosis of these cells underwent evaluation via flow cytometry, CCK8 assays, Fe²⁺ assays, along with Western blotting. Differential expression analysis and random forest results identified Arachidonate 15-Lipoxygenase (ALOX15) as a core gene associated with DPNP-related ferroptosis. Subsequently, we verified elevated levels of iron death and ALOX15 expression in neurons using both in vivo and in vitro models. Notably, silencing ALOX15 markedly inhibited high glucose-induced ferroptosis within SH-SY5Y cells and restored neuronal viability. Our findings indicate that ALOX15 promotes the development of DPNP by mediating neuronal ferroptosis, providing new insights into the role of ALOX15 as a biomarker for DPNP while proposing innovative strategies to prevent and treat DPNP.