Tirzepatide Attenuates Polystyrene Nanoplastic-Induced Testicular Injury by Preserving the Blood–Testis Barrier and Suppressing Pyroptosis in Rats

Polystyrene nanoplastic (PSNP) contaminants are widespread in the environment with potential adverse effects on male reproductive health. This study investigated the molecular mechanisms underlying PSNP-induced testicular dysfunction in rats and evaluated the protective effects of pirfenidone (PF) and tirzepatide (TZP). Twenty-four adult albino rats were included in the study. Eighteen rats received PSNP (1.5 mg/kg/day, orally) for 8 weeks, while six age-matched rats receiving deionized water by oral gavage served as negative controls. Beginning in week 5, PSNP-exposed rats were assigned to three groups (n = 6/group): vehicle-treated PSNP, PSNP+PF (100 mg/kg/day, orally), and PSNP+TZP (0.5 mg/kg/week, subcutaneously), with treatments continued for 4 weeks. PSNP exposure impaired testicular architecture, disrupted the blood–testis barrier, compromised steroidogenesis, and promoted testicular fibrosis. It also induced oxidative stress through dysregulation of the TXNIP/TRX system and enhanced pyroptosis, potentially through activation of the HMGB1/TLR4/NF-κB/NLRP3 signaling pathway. Treatment with either PF or TZP markedly attenuated PSNP-induced alterations, preserved blood–testis barrier integrity, improved steroidogenic function, and reduced fibrosis, oxidative stress, and pyroptosis. These protective effects were associated with modulation of the TXNIP/TRX system and suppression of HMGB1/TLR4/NF-κB/NLRP3-mediated pyroptotic signaling. Collectively, these findings identify PF and TZP as promising preclinical candidates for mitigating PSNP-induced testicular toxicity. Further mechanistic and translational studies are warranted to validate their potential role in protecting male reproductive health.