Melatonin Alleviates Acute Kidney Injury by Inhibiting NRF2/Slc7a11 Axis-Mediated Ferroptosis

Area of Science:

• Nephrology
• Cell Biology
• Pharmacology

Background:

• Acute kidney injury (AKI) is a significant clinical challenge with poorly understood pathophysiology and limited effective treatments.
• Ferroptosis, a regulated cell death pathway involving iron and reactive oxygen species, has emerged as a key player in AKI pathogenesis.
• Melatonin (MT), a known antioxidant, has shown therapeutic potential in AKI, but its specific mechanism in mitigating ferroptosis remains unclear.

Purpose of the Study:

• To investigate the protective mechanism of melatonin against ferroptosis in acute kidney injury.
• To elucidate the role of the NRF2/Slc7a11 signaling pathway in melatonin's renoprotective effects.

Main Methods:

• Utilized in vivo mouse models of AKI induced by ischemia-reperfusion and folic acid.
• Employed in vitro studies using mouse tubular epithelial cells (MTEC) subjected to hypoxia/reoxygenation or erastin to induce ferroptosis.
• Performed RNA sequencing to analyze ferroptosis-related gene expression.
• Conducted NRF2 knockdown experiments to assess its role in ferroptosis and melatonin's efficacy.

Main Results:

• Melatonin treatment significantly improved serum biochemistry and kidney histopathology in vivo AKI models.
• Melatonin effectively rescued MTEC from ferroptosis induced by hypoxia/reoxygenation or erastin.
• Melatonin inhibited hypoxia/reoxygenation-mediated downregulation of NRF2 and upregulation of Slc7a11.
• NRF2 knockdown sensitized cells to ferroptosis and abolished melatonin's protective effect.

Conclusions:

• Melatonin prevents ferroptosis in acute kidney injury.
• The protective mechanism involves the activation of the NRF2/Slc7a11 axis.
• Melatonin represents a promising therapeutic agent for AKI by targeting ferroptosis.