Targeting PIM1 ameliorates sepsis-associated acute kidney injury through inhibiting ferroptosis

Sepsis-associated acute kidney injury (SA-AKI) is a major contributor to death in intensive care units (ICU). The proviral integration site for Moloney murine leukemia virus-1 (PIM1), possesses multiple cellular functions, its function and mechanism in SA-AKI remain unclear. PIM1 was found abnormally upregulated in kidney tissues of SA-AKI mice and LPS-triggered HK-2 cells. Our findings demonstrated that PIM1 protected sepsis-induced kidney injury via restraining Reactive Oxygen Species (ROS) and Ferroptosis. In vivo, upregulation of PIM1 effectively relieved sepsis-induced kidney dysfunction, kidney damage, mitochondrial damage, and redox imbalance. In vitro, PIM1 preserved mitochondrial function by restoring the level of mitochondrial membrane potential. Furthermore, PIM1 reduced iron accumulation and mitochondria ROS, inhibited acyl-CoA synthetase long chain family member 4 (ACSL4), ferritin heavy chain 1 (FTH1), prostaglandin synthase 2 (PTGS2) expression, restored glutathione (GSH) level and Glutathione Peroxidase 4 (GPx4) expression, and regulated lipid metabolism to inhibit sepsis-related Ferroptosis. Our findings imply that PIM1 protects SA-AKI via mitochondrial ROS and the Ferroptosis pathway, which provides novel insights for PIM1 as a promising target for kidney protection during sepsis.

Acute kidney injury; Ferroptosis; Oxidative stress; PIM1; Sepsis.