Kaempferol inhibits oxidative stress-induced ferroptosis via the ROS/P38MAPK pathway to delay intervertebral disc degeneration: a combinatorial study of cell, animal, and transcriptomic evidence

Intervertebral disc degeneration (IVDD) is a well-known major contributor to lower back pain and has become a significant challenge in the field of public health. Kaempferol (KAE) is a naturally occurring flavonoid compound found in various herbs and plant families, known for its potent anti-inflammatory and antioxidant pharmacological effects. Ferroptosis is a recently discovered form of cell death characterized by iron dependence and the uncontrollable accumulation of lipid peroxides. Studies have reported that the activity of nucleus pulposus (NP) cells in IVDD is influenced by Ferroptosis, which is one of the contributing factors to IVDD. As of now, the therapeutic effects and mechanisms of KAE in IVDD remain unclear. To elucidate the therapeutic effects and potential mechanisms of KAE in IVDD, we established an in vitro NP cell degeneration model and found that KAE could delay the degeneration process of NP cells. Then we performed transcriptome Sequencing and identified that Ferroptosis and the p38 MAPK pathway might be potential targets through which KAE exerts its therapeutic effects. Further in vitro experiments revealed that KAE could inhibit ROS production, thereby suppressing the p38 MAPK pathway to delay the progression of NP cell Ferroptosis, thus protecting NP cells from degeneration. We then used molecular docking to validate the tight binding of KAE to ferroptosis-related targets. Finally, we further confirmed the potential of KAE in protecting against IVDD in vivo. In summary, our study demonstrates that KAE may be a promising candidate drug for the treatment of IVDD.