Mesaconine alleviates hyperalgesia in CFA-induced mice by modulating YAP1 to suppress cell ferroptosis within the...

Chronic inflammatory pain, often arising from trauma, arthritis, or infections, is a prevalent type of chronic pain. Clinically, it is characterized by hyperalgesia, along with spontaneous and persistent pain. Research shows that the neuron loss in the spinal dorsal horn is key to maintaining persistent hyperalgesia in multiple chronic pain conditions. Mesaconine (MES), a C₁₉ diterpenoid alkaloid from Aconitum carmichaeli, demonstrates significant anti-inflammatory and analgesic properites.

In this study, we focused on ferroptosis, a form of programmed cell death, to investigate the effect of MES on Complete Freund's adjuvant (CFA)-induced chronic inflammatory pain in mice and to investigate its underlying mechanism.

MES alleviates CFA-induced chronic inflammatory pain, suppresses ferroptosis in the spinal cord, and reduces the loss of Glutamic acid decarboxylase 65 (GAD65)-positive neurons. Additionally, separate experimental groups received ferroptosis inhibitor Liproxstatin-1 (LIP) and the ferroptosis inducer Erastin (ERA). Both MES and LIP inhibited spinal ferroptosis, reduced neuronal loss, enhanced GAD65 expression, and mitigated hyperalgesia. In contrast, ERA abolished the protective effects of MES. Further proteomic analysis revealed that MES treatment markedly down regulated the Yes associated protein (YAP) 1 protein expression and inhibited its nuclear translocation. In addition, pharmacological inhibition and activation confirmed that YAP1 is a critical target through which MES suppresses CFA-induced ferroptosis and chronic inflammatory pain.

This study demonstrates that MES suppresses ferroptosis in spinal cord cells by regulating YAP1 activity, thereby reducing neuronal loss, increasing GAD65 expression, and inhibiting neuroinflammation. This restores the central inhibitory effects of the spinal cord, ultimately alleviating hyperalgesia.