Ferulic acid/GRB2/NF-κB signaling pathway that alleviates ferroptosis-induced apoptosis of nucleus pulposus cells is a potential mechanism for intervertebral disc degeneration

Background: Intervertebral disc degeneration (IDD) is one of the main causes of low back pain, and its pathogenesis involves the gradual loss of nucleus pulposus cells (NPCs). However, the molecular mechanisms linking these pathways are not yet fully understood. Objective: This study aims to investigate the role of ferulic acid (FA) in IDD and its potential mechanisms of action, providing potential therapeutic targets for IDD. Methods: Analysis of 10 common traditional Chinese medicine prescriptions for lumbar disc herniation revealed that ferulic acid (Ferulic acid, FA) is a major active pharmaceutical ingredient. CCK8 confirmed that FA promotes the proliferation of NP cells. Edu results showed that FA promotes NP cell proliferation, while ferroptosis inhibits NP proliferation. Moreover, FA can alleviate the inhibitory effect of ferroptosis on NP cell proliferation. Subsequently, animal experiments confirmed that FA alleviates IDD in rats, and safranin O-fast green staining results confirmed that FA has a role in alleviating IDD lesions. Analysis of the GSE15227 and GSE23130 datasets showed that GRB2 is a hub gene in the progression of IDD, and molecular docking results showed that FA can bind to GRB2. WB demonstrated that FA significantly increased the expression of IκBα in ferroptosis-induced NP cells, thereby promoting proliferation. Meanwhile, the addition of the NF-κB agonist (TNF-α) significantly reduced IκBα expression and significantly inhibited NP cell proliferation. Results: FA significantly inhibited ferroptosis markers and NPC proliferation in NPCs. GRB2 is one of the hub genes of IDD, and molecular docking results showed that FA has binding sites with GRB2. Meanwhile, FA upregulated IκBα, inhibiting the nuclear translocation of NF-κB and its downstream pro-inflammatory cytokines. Conclusion: FA can significantly alleviate the progression of IDD. FA may inhibit NPC inflammation and lipid peroxidation through the GRB2/NF-κB pathway, The FA-GRB2/NF-κB axis is a potential therapeutic target for intervertebral disc degeneration.