Pharmacological inhibition of STING-mediated GPX4 autophagic degradation by 4-octyl itaconate ameliorates sepsis-induced acute kidney injury.

Summary

In CLP-induced sepsis-AKI, 4‑octyl itaconate reduced tubular ferroptosis, inflammation, and oxidative stress, improving renal function comparably to ferrostatin‑1. Mechanistically, 4‑OI both suppressed STING activation (Nrf2-independent) and reduced STING transcription (via Nrf2), preventing STING-mediated autophagic degradation of GPX4 and limiting ROS.

Key Findings

• CLP increased renal inflammation, oxidative stress, and ferroptosis; 4‑OI and ferrostatin‑1 both mitigated ferroptosis and improved renal function.
• In LPS-stimulated HK‑2 cells, 4‑OI reduced ferroptosis and inflammatory cytokines.
• 4‑OI suppressed STING pathway activation (Nrf2-independent) and reduced STING transcription via Nrf2, preventing STING-mediated autophagic degradation of GPX4 and limiting ROS.

Clinical Implications

Targeting STING and ferroptosis could prevent or mitigate sepsis-associated AKI. 4‑octyl itaconate merits translational evaluation as a nephroprotective adjunct in sepsis.

Limitations

• Preclinical animal and cell models only; no human validation or survival outcomes reported.
• Potential off-target effects and dosing/PK of 4‑OI in sepsis are not characterized.

Future Directions

Validate the STING–GPX4 axis in human sepsis-AKI, define 4‑OI pharmacology and safety, and test efficacy in large-animal models toward early-phase clinical trials.