Andrographolide attenuates sepsis-induced acute kidney injury by inhibiting ferroptosis through the Nrf2/FSP1 pathway

Area of Science:

• Nephrology
• Cell Biology
• Pharmacology

Background:

• Sepsis triggers systemic inflammation and acute kidney injury (AKI), a severe complication.
• Ferroptosis, a form of iron-dependent cell death, contributes to AKI pathogenesis.
• Andrographolide (AG), from *Andrographis paniculata*, shows promise for kidney disease treatment.

Purpose of the Study:

• To investigate AG's mechanism in attenuating sepsis-associated AKI (S-AKI).
• To determine if AG inhibits ferroptosis in renal tubular cells via the Nrf2/FSP1 pathway.

Main Methods:

• Established rat models of S-AKI (cecum ligation and puncture) and *in vitro* LPS-induced HK-2 cells.
• Administered AG and assessed kidney injury markers (creatinine, BUN, KIM-1).
• Evaluated ferroptosis markers (iron, lipid peroxidation, SLC7A11, GPX4) and mitochondrial integrity. Utilized Nrf2 siRNA and ferroptosis inhibitor (Fer-1).

Main Results:

• AG reduced kidney injury indicators and prevented ferroptosis in septic rats and HK-2 cells.
• AG inhibited iron accumulation, lipid peroxidation, and modulated SLC7A11/GPX4 levels.
• AG preserved mitochondrial structure and its protective effects were linked to the Nrf2/FSP1 pathway.

Conclusions:

• AG alleviates S-AKI by inhibiting ferroptosis in renal tubular epithelial cells.
• The Nrf2/FSP1 pathway is crucial for AG's protective effects against ferroptosis.
• AG represents a potential therapeutic agent for S-AKI, targeting ferroptosis.