SERPINE1 Drives Neuropathic Pain in a Resiniferatoxin-Induced Model via AKT-Mediated Neuronal Apoptosis

Postherpetic neuralgia (PHN) is a persistent neuropathic pain condition resulting from varicella-zoster virus reactivation, yet remains inadequately treated. Here, we elucidate a pathogenic function of Serpin Family E Member 1 (SERPINE1) in neuropathic pain using a resiniferatoxin (RTX)-induced neuropathic pain to simulate PHN. RTX administration triggered sustained mechanical allodynia and thermal hyposensitivity, accompanied by damage in the dorsal root ganglion (DRG) and sciatic nerve. Transcriptomic analysis identified SERPINE1 as a prominently upregulated gene in DRG following RTX challenge. Pharmacological inhibition of SERPINE1 with TM5441 alleviated pain-related behaviors in a dose-dependent manner, restored vanilloid 1 (TRPV1)-positive neuronal populations, and mitigated ultrastructural nerve pathology. Mechanistically, SERPINE1 suppression attenuated neuronal apoptosis (lowered caspase‑3) in the DRG. This anti‑apoptotic effect was associated with inhibition of the AKT pathway, evidenced by decreased AKT phosphorylation in both DRG tissues from RTX‑treated rats and RTX‑stimulated SH‑SY5Y cells. Our findings demonstrate that SERPINE1 drives neuropathic pain in the RTX model and highlight its pharmacological inhibition as a promising therapeutic strategy.