Injectable ROS homeostasis protective hydrogel inhibiting microglial ferroptosis through the Nrf2/Slc7a11/Gpx4 to alleviate neuropathic pain and promote spinal cord injury repair
Lu Li, Yu Cao, Xiangsheng Zhang, Jiayi Guo, Ziqiang Lin, Pengyu Zhou, Chuyin Chen, Jia-Hao Chen, Yike Liu, Danzhi Luo, Jiurong Chen, Yingdong Deng, Peng Sun, Zhiwen Zeng, Jun Zhou
Abstract
Spinal cord injury (SCI) induced neuropathic pain (NP) remains a major clinical challenge due to persistent neuroinflammation and oxidative stress. We developed an injectable methacrylated and thiolated gelatin hydrogel loaded with quercetin (MSQ) to synergistically scavenge reactive oxygen species (ROS) and inhibit microglial ferroptosis for NP alleviation and neural repair. The MSQ hydrogel exhibited rapid photocrosslinking, sustained quercetin release, and robust ROS scavenging via thiol groups and quercetin, maintaining intracellular redox homeostasis. MSQ attenuated LPS-induced ferroptosis in BV2 microglia by upregulating Nrf2 expression, promoting its nuclear translocation, and activating the Slc7a11/Gpx4 pathway, thereby reducing lipid peroxidation and inflammatory cytokine release. Network pharmacology and molecular dynamics simulations confirmed quercetin's high-affinity binding to Nrf2. In a murine SCI model, MSQ implantation significantly reduced lesion area, suppressed microglial ferroptosis, and decreased pro-inflammatory mediators (TNFα, IL-1β, IL-6), while enhancing neuronal survival (Nissl/NeuN + cells) and axonal regeneration (MAP2/5-HT + expression). Motor functional recovery assays revealed improved BMS scores, gait regularity, and mechanical/thermal pain thresholds in MSQ-treated mice. This study highlights MSQ hydrogel as a multifunctional therapeutic platform that targets ROS homeostasis and microglial ferroptosis via the Nrf2/Slc7a11/Gpx4 axis, offering a promising strategy for post-SCI NP management and neural regeneration.