Targeting sphingosine‐1‐phosphate receptor‐2 attenuates spinal cord injury by preventing neuronal ferroptosis

Background and Purpose Spinal cord injury (SCI) imposes severe physiological and psychological burdens on patients. We investigated the role of sphingosine‐1‐phosphate receptor 2 (S1P 2 receptor) in contusive spinal cord injury and evaluated the therapeutic effects of an S1P 2 receptor antagonist S118 (C₁₉H₁₄Cl 2 FN₇O) in a rat model of SCI. Experimental Approach The SCI model was established using a 10 g weight dropped onto the T10 vertebrae in female rats. After functional testing, spinal cords were harvested for biochemical and histopathological assays at different time points. Nissl and Prussian blue staining were used to analyse neuronal death. Neuronal ferroptosis in spinal cords was examined using transmission electron microscopy, and lipid peroxidation in the cultured neurones was analysed. Key Results After SCI, S1P (Sphingosine 1‐phosphate) was released from crushed spinal cords and subsequently activated the neuronal S1P 2 receptor to increase lipid peroxidation, which injured neurones via inducing neuronal ferroptosis through the P‐ERK/ERK/ACSL4 pathway, resulting in limb paralysis. S1P 2 receptor inhibition significantly blocked S1P 2 receptor activation and attenuated neuronal ferroptosis. Thus, S1P 2 receptor was a therapeutic target for the treatment of SCI. Systemic administration of the S1P 2 receptor antagonist S118 (C₁₉H₁₄Cl 2 FN₇O) effectively promoted locomotor function recovery by attenuating neuronal ferroptosis in rat spinal cords. S118 impeded neuronal ferroptosis by inhibiting lipid peroxidation. Conclusions and Implications Contusive SCI is characterised by neuronal loss due to S1P 2 receptor activation in spinal neurones. S1P 2 receptor activation increases lipid peroxidation, which induces neuronal ferroptosis. S118 (C₁₉H₁₄Cl 2 FN₇O) improves locomotor functional recovery by preserving the spinal cord structure after SCI.