PAFAH2 suppresses synchronized ferroptosis to ameliorate acute kidney injury

Area of Science:

• Biochemistry
• Cell Biology
• Nephrology

Background:

• Synchronized ferroptosis drives nephron loss in acute kidney injury (AKI).
• Mechanisms and propagation signals of synchronized ferroptosis in renal tubular injury are not fully understood.

Purpose of the Study:

• To investigate the role of platelet-activating factor (PAF) and related phospholipids in mediating synchronized ferroptosis and contributing to AKI.
• To explore the potential of targeting PAF signaling for AKI intervention.

Main Methods:

• Investigated the role of PAF and PAF-like phospholipids (PAF-LPLs) in ferroptosis.
• Utilized genetic knockout and pharmacological inhibition of PAF-acetylhydrolase (PAFAH2).
• Administered wild-type and mutant PAFAH2 protein in vivo.

Main Results:

• PAF and PAF-LPLs were identified as mediators of synchronized ferroptosis, causing biomembrane instability and signaling death to neighboring cells.
• Genetic or pharmacological inhibition of PAFAH2 increased PAF, augmented ferroptosis, and worsened ischemia/reperfusion (I/R)-induced AKI.
• Intravenous administration of wild-type PAFAH2 protein, but not inactive mutants, prevented synchronized tubular cell death, nephron loss, and AKI.

Conclusions:

• PAF and PAF-LPLs are key mediators of synchronized ferroptosis in AKI.
• PAFAH2 acts as a suppressor of this ferroptosis cascade.
• PAFAH2 protein administration represents a potential therapeutic strategy for preventing AKI.