Cyclophosphamide (CP) is a chemotherapeutic agent that induces oxidative stress causing multiple organ damage. Sacubitril/valsartan, is a combined formulation of neprilysin inhibitor (sacubitril) and angiotensin II receptor blocker (valsartan), that induces the protective effect of brain natriuretic peptide. The aim of the current study is to investigate the prophylactic impacts of sacubitril/valsartan versus valsartan against CP-induced lung toxicity in rats. Rats were assigned randomly into 6 groups; control; received corn oil (2 ml/kg/day; p.o. for 6 days), sacubitril/valsartan (30 mg/kg; p.o. for 6 days), valsartan (15 mg/kg; p.o. for 6 days), CP (200 mg/kg; i.p. on day 5), sacubitril/valsartan + CP (30 mg/kg; p.o. for 6 days, 200 mg/kg; i.p. single dose on day 5, respectively), valsartan + CP (15 mg/kg; p.o. for 6 days, 200 mg/kg; i.p. single dose on day 5, respectively). Both sacubitril/valsartan and valsartan produced a significant decrease in the inflammation and fibrosis markers in the BALF, in comparison with the CP group. Both sacubitril/valsartan and valsartan produced an apparent decrease in the relative genes expression of miR-150-3p and NF-κB, as well as a significant decrease in the relative expression of P38 and ERK1/2 MAPKs and an increase in the relative gene expression of Nrf-2, compared to CP group. Intriguingly, sacubitril/valsartan , showed subtle superiority in almost all investigated parameters, compared to valsartan. In conclusion, sacubitril/valsartan effectively abrogated the CP induced lung inflammation and fibrosis, providing a potential promising protection that could be linked to their ability to inhibit miR-150-3p via inhibition of NF-κB and MAPK signaling pathways.

Background: Disrupted iron homeostasis is increasingly perceived as a key driver of major depressive disorder pathogenesis; hence, targeting ferroptotic cascades may reveal novel therapeutic targets. This study evaluated the neuroprotective potential of the oral iron chelator deferasirox (DEF) against chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and cognitive deficits in Wistar rats. Methods: We specifically explored whether DEF could provide neuroprotection by targeting ferroptotic and oxidative stress pathways. Male Wistar rats were exposed to a 6-week CUMS protocol and treated with DEF (10, 20, or 40 mg/kg). Results: CUMS-exposed rats exhibited significant anhedonia, behavioral despair, and impaired spatial and recognition memory. Further analyses revealed a reduction in colonic and choroid plexus occludin, reflecting compromised structural integrity of both the intestinal and blood-CSF barriers, accompanied by enhanced hippocampal iron accumulation with increased Acyl-CoA synthetase long-chain family member 4 (ACSL4), Acyl-CoA synthetase family member 2 (ACSF2), and citrate synthase expression, alongside exaggerated oxidative stress and deficient neuroprotective mediators, specifically BDNF and synaptophysin, and increased neurofibrillary tangle (NFT) deposition, collectively exacerbating neurodegenerative pathology. DEF treatment ameliorated most of these effects, significantly reducing iron deposition, attenuating ferroptosis-related signaling, reducing oxidative stress, diminishing the ongoing neurodegeneration, and replenishing the depleted pool of BDNF and synaptophysin, which was accompanied by a reduction in depressive-like symptoms and improved cognitive functions. Conclusions: These findings support a link between ferroptosis-related signaling and depression-like phenotypes, reinforcing the concept of a metal-driven component in depression pathophysiology and offering a mechanistic rationale for further exploring targeting ferroptotic pathways and central iron regulation as potential targeted strategies in depression management.