PARP1 Contributes to Neuropathic Pain Via GPX4-dependent Sensory Neuron Ferroptosis in Nerve-Injured Mice

Neuropathic pain is associated with sensory neuron injury, and ferroptosis has been implicated in neuronal damage and death. However, the regulatory mechanism of ferroptosis in neuropathic pain remains unclear. This study aimed to investigate poly-(ADP-ribose) polymerase 1 (PARP1) in regulating sensory neuron ferroptosis and to assess its potential therapeutic role in neuropathic pain. A chronic constriction nerve injury (CCI) mouse model was established to examine how ferroptosis in sensory neurons contributes to CCI-induced neuropathic pain. We analyzed the expression of ferroptosis-related key gene (GPX4, FPN1, FSP1, TFR1, DMT1) and ferroptosis in dorsal root ganglion (DRG) neurons, along with PARP1 activity. Blocking PARP1 activity with PJ34 or olaparib, or conditionally knocking out neuronal PARP1, was performed to assess effects on GPX4 expression, ferroptosis, and neuropathic pain behavior. Nerve injury downregulated GPX4 expression and enhanced ferroptosis in DRG neurons, accompanied by increased PARP1 activity. Using sensory neuron-specific PARP1 conditional knockout mice, we demonstrated that neuronal PARP1 deletion upregulated GPX4 expression, reduced ferroptosis, and alleviated neuropathic pain-like behaviors. Blocking GPX4 activity induced pain sensitization in normal mice. Inhibition of ferroptosis or administration of PARP1 inhibitors significantly alleviated pain-like behaviors in CCI mice. Following nerve injury, PARP1 overactivation drives neuropathic pain by suppressing GPX4 and promoting ferroptosis in DRG neurons. Conditional knockout or pharmacological inhibition of PARP1 reversed these effects and alleviated pain. Thus, the PARP1-GPX4 axis represents a promising therapeutic target.