Otilonium bromide ameliorates paclitaxel-induced peripheral neuropathy by targeting phosphatase PPM1A

Abstract Paclitaxel (PTX)-induced peripheral neuropathy (PIPN) is a severe side effect lacking effective treatment, largely due to its complex and poorly understood pathogenesis. Here, we observed the pathological inhibition of phosphatase PPM1A activity in the dorsal root ganglia (DRG) tissues of PIPN mice. We also found that otilonium bromide (OB), as a PPM1A activator, ameliorated the PIPN-like pathology in mice, as evidenced by the alleviation of sensory dysfunction, myelin sheath injury, intraepidermal nerve fiber loss and vascular lesions. Using PPM1A-specific knockdown mice, we demonstrated that OB suppresses pro-inflammatory M1 macrophage polarization in the DRG through the PPM1A/NF-κB/NLRP3/IL-1β pathway, thereby alleviating axonal degeneration and neuronal apoptosis. In vitro experiments revealed that PTX-damaged DRG neurons release high-mobility group box 1 (HMGB1) to promote pro-inflammatory macrophage polarization, while OB disrupts this neuron-macrophage interaction by limiting HMGB1 release and subsequent macrophage activation. Together, our findings highlight PPM1A activation as a promising therapeutic strategy for PIPN and identify OB as a potential agent for treating this clinical side effect. Graphical Abstract