Cilastatin Protects Against Chemotherapy-Induced Neuropathy via the FKBP51/DPEP1 Axis: Confocal Insights into Protein Dynamics

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-α 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-α 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.