Oxaliplatin-induced peripheral neurotoxicity (OIPN) represents a major challenge in cancer therapy, characterized by dorsal root ganglia (DRG) inflammation and disruption of neuro-glio-vascular unit function. In this study, we investigated the involvement of the scaffold protein IQ Motif Containing GTPase Activating Protein 1 (IQGAP1) and dehydropeptidase-1 (DPEP1) in the DRG response to oxaliplatin (OxPt) and the modulatory effect of cilastatin. Behavioral assessment showed a robust nocifensive response to cold stimuli in OxPt-treated rats, attenuated by cilastatin co-treatment. Our confocal study revealed different cellular and subcellular expression patterns of IQGAP1 and DPEP1 in neurons, glia, and endothelial cells, where both signals overlap approximately one-third. OxPt enhanced cytosolic aggregation of IQGAP1 in neurons and upregulation of signal in glia, accompanied by co-expression of TNFα and IL-6, indicating involvement in the inflammatory process. DPEP1 showed altered subcellular distribution in OxPt-treated animals, suggesting a potential role in the inflammatory cascade. Notably, IQGAP1 expression was diminished in endothelial membranes under OxPt, while cilastatin preserved endothelial IQGAP1-CD31 colocalization, suggesting partial restoration of blood-nerve barrier integrity. These findings identify IQGAP1 and DPEP1 as key players in DRG inflammation and position cilastatin as a promising modulator of OIPN through neuro-glio-vascular stabilization.

Dorsal root ganglion (DRG) neuroinflammation is a hallmark feature of oxaliplatin-induced peripheral neuropathy (OIPN), a dose-limiting side effect with poorly understood molecular mechanisms. In this study, we investigated the protective potential of cilastatin (CIL), a dipeptidase 1 (DPEP1) inhibitor, while elucidating the regulatory roles of FK506-binding protein 51 (FKBP51) and DPEP1 in OIPN pathogenesis. Behavioral allodynia was evaluated using the acetone test in an oxaliplatin (OxPt) rat model. Lumbar DRGs were imaged via advanced confocal microscopy (Zeiss LSM980 Airyscan 2, Zeiss, Oberkochen, Germany) and analyzed using Fiji 1.54t software to determine fluorescence intensity, subcellular distribution, and co-localization metrics (Pearson’s and Manders’ coefficients). OxPt administration induced marked downregulation and cytoplasmic-to-nuclear translocation of FKBP51 within DRG neuronal and glial compartments. Notably, FKBP51 frequently co-localized with DPEP1 and the pro-inflammatory cytokines TNF-$\alpha$ and IL-6. DPEP1 was strongly expressed in DRG neurons, where it exhibited enhanced perinuclear localization. Concomitant CIL treatment significantly reversed these alterations by attenuating the OxPt-induced cell-type- and compartment-specific changes in FKBP51 and DPEP1 distribution, suppressing TNF-$\alpha$ and IL-6 expression, and preventing GFAP overexpression. These findings identify a novel interplay between FKBP51 and DPEP1 within the DRG during OIPN-elicited neuroinflammation, potentially linking stress protein signaling to pro-inflammatory cytokine activation. Consequently, CIL represents a promising therapeutic candidate to prevent chemotherapy-induced neurotoxicity.