# Potential gonadal-beneficial effect of sitagliptin against paclitaxel-induced testicular dysfunction via mediating PERK/CHOP/NLRP3/Sestrin2 signaling pathway

## TL;DR

Sitagliptin may protect testicles from paclitaxel damage by reducing inflammation and stress through a specific signaling pathway.

## Contribution

The study reveals a novel protective mechanism of sitagliptin against testicular dysfunction caused by paclitaxel.

## Key findings

- Sitagliptin improves sperm count, motility, and viability while reducing abnormalities.
- Sitagliptin reduces inflammation and oxidative stress by modulating the PERK/CHOP/NLRP3/Sestrin2 pathway.
- Sitagliptin shows anti-apoptotic effects by decreasing cleaved caspase-3 and cytochrome c levels.

## Abstract

Paclitaxel (PTX) is broadly prescribed to treat various malignancies. However, it induces negative impacts on many organs, including testes. This study explored the beneficial role of sitagliptin (SIT) in PTX-provoked testicular damage and the underlying mechanisms. Rats were allocated into four groups: (I) control, (II) PTX, (III) PTX + SIT5, and (IV) PTX + SIT10. Histopathological and ultrastructural analyses were conducted along with sperm analysis. Immunohistochemical examinations of NOD-like receptor protein 3 (NLRP3), cleaved caspase-3, caspase-3, cytochrome c (Cyt.c), and interleukin-1 beta (IL-1β) were assessed. Serum testosterone and testicular 17β-hydroxy steroid dehydrogenase (17β-HSD), sestrin2, phosphorylated protein kinase R-like ER kinase (pPERK), and C/EBP homologous protein (CHOP) were determined. SIT induced a remarkable increase in sperm count, motility, and viability, with a pronounced decline in sperm abnormality compared to PTX group. SIT increased testosterone and 17β HSD levels. SIT elevates sestrin2, reduced glutathione (GSH), and catalase, and reduces malondialdehyde (MDA), reflecting its antioxidant action. SIT mitigates ER stress via diminishing pPERK and CHOP. SIT reduces NLRP3 and IL-1β levels, clarifying its anti-inflammatory action. SIT decreases cleaved caspase-3, caspase-3, and Cyt.c levels, verifying its anti-apoptotic features. Overall, SIT ameliorated PTX-provoked testicular dysfunction via mediating PERK/CHOP/NLRP3/Sestrin2 signaling pathway.