Gentisic acid ameliorates lumbar disc herniation by regulating M1/M2 Polarization via the MAPK14/S100A9/Rac1/2 pathway.

Traditional Chinese medicine is gaining prominence in lumbar disc herniation (LDH) management, but the mechanisms of its active compounds and their molecular targets remain largely unclear. Herein, we aim to elucidate the therapeutic mechanism of Gentisic acid by investigating its role in regulating S100A9 in LDH. Clinical analysis reveals that S100A9 expression and inflammatory levels correlat positively with LDH severity. S100A9 is found to promote M1 macrophage polarization and impair dorsal root ganglion (DRG) neuronal activity. Mechanistically, Gentisic acid binds to MAPK14, downregulates S100A9 via MAPK14, and then suppresses M1 polarization, enhances neuronal autophagic flux, and improves neuronal viability through the S100A9/Rac1/2 pathway. In vivo experiments demonstrate that Gentisic acid ameliorates disc injury, improves neurological function, and alleviates pain in a rat LDH model, with efficacy comparable to celecoxib. These results suggest that Gentisic acid could alleviate LDH symptoms by modulating macrophage polarization and autophagy through the MAPK14/S100A9/Rac1/2 axis, offering a promising therapeutic strategy for LDH.