# Nano-Cilostazol Mitigates Cisplatin-Induced Nephrotoxicity in Rats via Modulation of Oxidative Stress, Apoptosis, Pyroptosis, and miRNA-155 Signaling

## TL;DR

Nano-Cilostazol protects rat kidneys from cisplatin damage by reducing oxidative stress, inflammation, and cell death pathways.

## Contribution

Nano-Cilostazol shows novel renoprotective effects via modulation of multiple pathways including miRNA-155 signaling in cisplatin-induced nephrotoxicity.

## Key findings

- Nano-Cilostazol reduced oxidative stress and restored antioxidant defenses in cisplatin-treated rats.
- Nano-Cilostazol inhibited apoptosis, pyroptosis, and inflammatory pathways in renal tissue.
- Nano-Cilostazol downregulated miRNA-155 and modulated JAK2/STAT3 signaling in cisplatin-induced nephrotoxicity.

## Abstract

Background: This study investigated the renoprotective potential of Nano-Cilostazol against cisplatin (CIS)-induced renal injury in male rats and explored its molecular mechanisms. Our results showed that Nano-Cilostazol has a favorable physicochemical characteristic, including a mean particle size of approximately 101 nm, narrow polydispersity, and high stability. FTIR analysis indicated successful drug entrapment, preserving functional groups and enhancing hydrogen bonding. Docking analysis showed that cilostazol had stronger binding affinities than disulfiram against seven acute kidney injury-related targets. Interaction profiling confirmed stable binding through hydrogen bonding, hydrophobic, and π-interactions with BAX, ASC, GSDMD, KIM-1, JAK2, NLRP3, and miRNA-155. In vivo, CIS administration led to marked renal dysfunction, showing up as significant elevations in serum urea, creatinine, cystatin-C, CRP, and NGAL which indicated by severe histopathological damage. Co-treatment with Nano-Cilostazol significantly lessened renal functional impairment biochemically and histopatologically. Nano-Cilostazol markedly reduced lipid peroxidation and oxidized glutathione while also restoring antioxidant defenses like superoxide dismutase and catalase, with total and reduced glutathione. Additionally, Nano-Cilostazol attenuated renal inflammation, inhibiting NF-κB activation, lowering pro-inflammatory cytokines (TNF-α and IL-1β), and downregulating inflammatory and injury-related genes. CIS-triggered apoptotic signaling was also mitigated, shown by increased caspase-3 and BAX expression with downregulation of BCL-2. Nano-Cilostazol significantly inhibited apoptosis and pyroptosis (NLRP3, ASC, GSDMD)-related pathways, modulated JAK2/STAT3 signaling, and downregulated miRNA-155 expression. In conclusion, Nano-Cilostazol offers potent protection against cisplatin-induced nephrotoxicity.