Journal of ethnopharmacology · 2026
Trifluoro-icaritin mitigates spared nerve injury-induced neuropathic pain by upregulating spinal α7nAChR through suppressing ferroptosis.
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Luo Fangting, Zhong Yebei, Meng Lingling, Chen Xuanjun, Li Weiwei, Wei Tianhao, Ma Haijuan, Huang Cheng
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Epimedium spp. Has served as a traditional analgesic herbal medicine in Chinese medicine for over two thousand years. Its active metabolite, icariin (ICT), along with its fluorinated derivative, trifluoro-icaritin (ICTF), has been shown in our previous research to alleviate neuropathic pain induced by spared nerve injury (SNI) through an α7 nicotinic acetylcholine receptor (α7nAChR)-dependent pathway.
AIM OF THE STUDY: Neuropathic pain remains a significant and unresolved health issue. Ferroptosis has recently been identified as a key, yet insufficiently explored, aspect, and the interaction between ferroptosis and the spinal cholinergic anti-inflammatory receptor α7nAChR remains entirely unknown. This study aims to investigate whether ferroptosis serves as a critical mechanistic link between α7nAChR and the analgesic effects of ICTF.
MATERIALS AND METHODS: A spared nerve injury (SNI) rat model was established to investigate neuropathic pain. Pain-related behaviors were assessed through paw withdrawal threshold (PWT) and CatWalk gait analysis. Western blotting and immunofluorescence were employed to detect protein expression and co-localization. Moreover, transcriptomic sequencing of spinal cord tissue was conducted to identify candidate pathways. To establish causality, two independent reverse validation approaches were utilized, including the administration of the ferroptosis agonist Erastin and intrathecal injection of adeno-associated virus to knock down α7nAChR.
RESULTS: Transcriptomic analysis revealed a significant enrichment of ferroptosis-associated gene signatures in SNI rat spinal cords, characterized by marked upregulation of pro-ferroptotic genes, including Cybb, Sat1, and Hmox1. Concurrently, SNI markedly decreased neuronal expression of α7nAChR and the ferroptosis-inhibitory enzyme GPX4. Treatment with ICTF (5.0 mg/kg, intraperitoneally), the optimal dosage screened in our prior study, effectively counteracted these alterations, accompanied by attenuation of iron overload, lipid peroxidation, and oxidative stress within the spinal cord. Reverse validation further demonstrated that Erastin abolished the analgesic and motor-improving effects of ICTF, while concurrently suppressing α7nAChR and GPX4 expression. Moreover, α7nAChR knockdown produced comparable effects, negating ICTF-mediated benefits and further reducing GPX4 levels.
CONCLUSION: We found that spinal ferroptosis is markedly activated in SNI rats, thereby exacerbating neuroinflammation and mechanical allodynia. Importantly, ferroptosis suppresses the expression of α7nAChR, while ICTF interrupts this vicious cycle by upregulating α7nAChR, inhibiting ferroptosis-related iron accumulation, lipid peroxidation, and the downregulation of GPX4, ultimately alleviating SNI-induced neuropathic pain. This study offers a scientific interpretation of the traditional use of Epimedium-derived active compounds for treating neuropathic pain at the modern molecular mechanism level.
AIM OF THE STUDY: Neuropathic pain remains a significant and unresolved health issue. Ferroptosis has recently been identified as a key, yet insufficiently explored, aspect, and the interaction between ferroptosis and the spinal cholinergic anti-inflammatory receptor α7nAChR remains entirely unknown. This study aims to investigate whether ferroptosis serves as a critical mechanistic link between α7nAChR and the analgesic effects of ICTF.
MATERIALS AND METHODS: A spared nerve injury (SNI) rat model was established to investigate neuropathic pain. Pain-related behaviors were assessed through paw withdrawal threshold (PWT) and CatWalk gait analysis. Western blotting and immunofluorescence were employed to detect protein expression and co-localization. Moreover, transcriptomic sequencing of spinal cord tissue was conducted to identify candidate pathways. To establish causality, two independent reverse validation approaches were utilized, including the administration of the ferroptosis agonist Erastin and intrathecal injection of adeno-associated virus to knock down α7nAChR.
RESULTS: Transcriptomic analysis revealed a significant enrichment of ferroptosis-associated gene signatures in SNI rat spinal cords, characterized by marked upregulation of pro-ferroptotic genes, including Cybb, Sat1, and Hmox1. Concurrently, SNI markedly decreased neuronal expression of α7nAChR and the ferroptosis-inhibitory enzyme GPX4. Treatment with ICTF (5.0 mg/kg, intraperitoneally), the optimal dosage screened in our prior study, effectively counteracted these alterations, accompanied by attenuation of iron overload, lipid peroxidation, and oxidative stress within the spinal cord. Reverse validation further demonstrated that Erastin abolished the analgesic and motor-improving effects of ICTF, while concurrently suppressing α7nAChR and GPX4 expression. Moreover, α7nAChR knockdown produced comparable effects, negating ICTF-mediated benefits and further reducing GPX4 levels.
CONCLUSION: We found that spinal ferroptosis is markedly activated in SNI rats, thereby exacerbating neuroinflammation and mechanical allodynia. Importantly, ferroptosis suppresses the expression of α7nAChR, while ICTF interrupts this vicious cycle by upregulating α7nAChR, inhibiting ferroptosis-related iron accumulation, lipid peroxidation, and the downregulation of GPX4, ultimately alleviating SNI-induced neuropathic pain. This study offers a scientific interpretation of the traditional use of Epimedium-derived active compounds for treating neuropathic pain at the modern molecular mechanism level.