Empagliflozin attenuates sorafenib-promoted renal ferroptosis and inflammation by targeting cyclooxygenase-2/prostaglandin E2 axis

The increased risk of nephrotoxicity may impact the life quality and survival outcome in cancer patients receiving sorafenib therapy. Therefore, the development of novel strategy against sorafenib nephrotoxicity is an urgent work. Sodium-glucose co-transporter-2 (SGLT2) inhibitors such as empagliflozin have been approved for renal failure treatment. So far, the potential of empagliflozin against sorafenib nephrotoxicity has not yet been reported. The SGLT2 and apoptotic marker expressions in the sorafenib-treated renal proximal tubular cells (HK-2 cells) was investigated using immunoblot analysis. The cell viability was evaluated in HK-2 cells after sorafenib ± empagliflozin treatment using Alamar blue assay. The immunoblot analysis was applied to study the effect of sorafenib ± empagliflozin treatment on ferroptotic and proinflammatory stresses in HK-2 cells. The cell death, ferroptosis, lipid peroxidation, cytokine storm, and immune cells recruitments of kidneys was investigated in mice receiving a 28-day sorafenib ± empagliflozin administration using histopathological analyses. Sorafenib exposure dose-dependently upregulated SGLT2 in HK-2 cells, and empagliflozin significantly attenuated the sorafenib-induced cell death in HK-2 cells and mouse kidneys. Moreover, the sorafenib-stimulated iron deposition, oxidative DNA damage, lipid peroxidation, and glutathione peroxidase 4 (GPX4)/ SLC7A11 (xCT)-dependent ferroptosis were significantly alleviated by empagliflozin in mouse kidneys. The sorafenib-promoted cyclooxygenase-2 (COX-2)/prostaglandin E₂ (PGE₂) signaling as a ferroptosis driver was significantly blocked by empagliflozin in HK-2 cells and mouse kidneys. Empagliflozin also attenuated the sorafenib-stimulated-HMGB1/IL-1β proinflammatory signaling in vitro and in vivo. Furthermore, the sorafenib-promoted macrophage and neutrophil infiltrations were significantly reduced by empagliflozin in mouse kidneys. Collectively, empagliflozin may serve as a potent anti-ferroptotic and anti-inflammatory agent against sorafenib nephrotoxicity by targeting COX-2/PGE₂ axis.