Cytoplasmic HMGB1 induces renal tubular ferroptosis after ischemia/ reperfusion

As a damage-associated molecular pattern molecule, high-mobility group box 1 (HMGB1) is well-studied and is released from injured tubular epithelial cells to trigger cell death. However, the role of intracellular HMGB1 induced cell death during acute kidney injury (AKI) is poorly understood. We showed that cytosolic HMGB1 induced ferroptosis by binding to acyl-CoA synthetase long-chain family member 4 (ACSL4), the driver of fer-roptosis, following renal ischemia/reperfusion (I/R). Both mouse and human kidneys with acute tubular injury were characterized by nucleocytoplasmic translocation of HMGB1in tubular cells. Pharmacological inhibition of HMGB1 nucleocytoplasmic translocation and deletion of HMGB1 in tubular epithelial cells in mice inhibited I/R-induced AKI, tubular ferroptosis, and inflammation compared to those in controls. Co-immunoprecipitation and serial section staining confirmed the interaction between HMGB1 and ACSL4. Taken together, our results demonstrated that cytoplasmic HMGB1 is essential for exacerbating inflammation-associated cellular injury by activating renal tubular ferroptosis via ACSL4 after I/R injury. These findings indicate that cytoplasmic HMGB1 is a regulator of ferroptosis and a promising therapeutic target for AKI.

Automated summary

In this study, it was demonstrated that cytosolic HMGB1 induces ferroptosis by binding to ACSL4, exacerbating cellular injury in acute kidney injury (AKI). Inhibition of HMGB1 nucleocytoplasmic translocation and deletion of HMGB1 in tubular epithelial cells reduced AKI, tubular ferroptosis, and inflammation in mice. Co-immunoprecipitation and serial section staining confirmed the interaction between HMGB1 and ACSL4. These findings suggest that cytoplasmic HMGB1 is a regulator of ferroptosis and a promising therapeutic target for AKI.