Liraglutide orchestrates ferroptosis defense against murine cisplatin acute kidney injury: NRF2 activation via both KEAP1-dependent and -independent mechanisms is essential for SLC7A11/GPX4 renoprotection

Abstract

Objective: Acute kidney injury (AKI) induced by oxidative stress, and recently associated with ferroptosis, represents a major complication of the chemotherapeutic cisplatin that often necessitates treatment cessation. The glucagon-like peptide 1 receptor (GLP1R) agonist liraglutide possesses reno-protective potential via its antioxidant character in different kidney injury settings while reducing iron overload in other models. Hence, we investigated the potential protective role of liraglutide in cisplatin-induced AKI targeting KEAP1-dependent and -independent ferroptosis pathways.

Methods: Rats were assigned to one of four groups: vehicle control, liraglutide control, cisplatin-induced AKI, and liraglutide-pretreated AKI. Renal function markers and histopathological changes were assessed. SLC7A11, NRF2, and KEAP1-canonical and non-canonical hubs were analyzed to elucidate the drug's molecular mechanisms on ferroptosis.

Results: Liraglutide significantly improved renal function, evidenced by the reduction of serum cystatin C, creatinine, and BUN, along with renal histological improvements. In the kidney, liraglutide activated/phosphorylated AKT, mTOR, and P62 to reduce KEAP1 and inactivated GSK3β to enhance NRF2-mediated GPX4 and SLC7A11 formation, thus inhibiting cisplatin-ferroptosis-triggered renal injury.

Conclusion: Therefore, liraglutide is a promising treatment candidate for attenuating cisplatin-induced AKI by SLC7A11/GPX4 trajectory through upregulating the AKT/mTOR/P62/KEAP1/NRF2 and AKT/GSK3β/NRF2 signaling pathways to increase GPX4 alongside with SLC7A11. Indeed, the GLP1R-mediated AKT activation acts as a potential target for Liraglutide reno-protective actions; hence, the GLP1R can be considered a therapeutic entity in such a renal injurious paradigm.