Linking GLP-1 activation with steroidogenesis, redox, endoplasmic reticulum stress, mitophagy, and the apoptotic regulatory network unlocks the emerging impacts of semaglutide on 5-fluorouracil-induced testicular toxicity.

AIMS: One of the recent growing complications of neoplastic chemotherapy that is considered a challenge in their therapeutic protocol is testicular dysfunction. The pathogenesis of testicular injury is multifactorial, involving various pathogenic mechanisms, including oxidative stress, endoplasmic reticulum stress (ERS), and mitochondrial dysfunction. Semaglutide (Sema), a GLP1 agonist, is repurposed nowadays in multiple conditions ascribed to its effectiveness in shielding against oxidative stress and ERS, along with boosting mitochondrial biogenesis. Accordingly, this study proposes to investigate the use of Sema as adjunctive therapy in a 5-fluorouracil (5-FU) treatment protocol to diminish its testicular dysfunction complications. MATERIALS AND METHODS: Rats were allocated into five groups. Group I: normal control group; Group II was injected with Sema (12 μg/kg, s.c.) once weekly for 30 days. Groups III (5-FU group), IV, and V were injected with 5-FU (20 mg/kg, every other day, i.p.) for 30 days. Group IV (Sema-treated group) was injected with Sema, while group V (Blocker group) was injected with exendin 9-39 (50 μg/kg, once weekly, I.V.). KEY FINDINGS: The results revealed that activation of GLP-1 attenuated 5-FU-induced testicular dysfunction by enhancing the PINK-1/Parkin axis and mitochondrial biogenesis, eliminating ERS-related proteins (PERK, ATF6, GRP78, and CHOP). Sema activated the Nrf2/HO-1 hub, improved steroidogenesis and spermatogenesis by elevating STAR/DAZL and serum FSH, LH, and testosterone levels. SIGNIFICANCE: This study highlighted the use of Sema as adjunctive therapy in the 5-FU treatment protocol to guard against the associated testicular dysfunction, via modulating oxidative stress, ERS, and mitochondrial dysfunction in the rat experimental model.