Klotho loss is linked to a cascade that triggers ferroptosis in kidney cells
In models of diabetic kidney disease, loss of the protective protein Klotho triggered the death of cells in the kidney filtration barrier through membrane lipid oxidation
On August 29, 2026, Advanced Science published a study in which biopsy samples linked this pathway to human disease, while experiments in mice and cultured human cells established the order of its components.
Podocytes are cells in the outer layer of the kidney filtration barrier that retain protein in the blood. In diabetic kidney disease, podocyte injury is associated with protein in the urine and declining kidney function. In this study, reduced levels of Klotho, a protein with protective functions in the kidney, initiated a sequence of events in podocytes.
In biopsy samples from people with the disease, diabetic mice, and cell experiments, reduced Klotho levels were accompanied by weaker protection against membrane lipid oxidation. When this protection weakens, iron accelerates lipid oxidation, and the cell may die through ferroptosis. Podocytes cultured under high-glucose conditions also contained fewer mitochondria and less glutathione, a substance involved in protecting cells from oxidation.
The authors searched for a protein that connects Klotho loss to this damage. They compared the podocyte protein profile with a list of genes associated with ferroptosis and identified SPARC. In diabetic mice with the SPARC gene knocked out, creatinine and the urinary albumin-to-creatinine ratio decreased. Suppressing SPARC in cells partially restored mitochondrial protection. When cells produced more SPARC under normal-glucose conditions, they developed signs of ferroptosis.
When Klotho levels fall, PKCα becomes active. This enzyme adds phosphate groups to other proteins. PKCα adds such a group to CUX1, a regulator of gene expression, and accelerates its degradation by the proteasome, the cellular system that disposes of proteins. CUX1 normally restrains transcription of the SPARC gene. When CUX1 levels fall, the cell produces more SPARC. SPARC interacts with TGFβ-RII, a receptor on the cell surface, and Smad proteins transmit its signal to genes. By altering PKCα and CUX1 separately, the authors showed how this sequence is associated with mitochondrial damage and ferroptosis.
PKCα became a candidate because of a 2019 study whose authors had already linked Klotho, PKCα, and podocyte injury in diabetes. The new study places CUX1 and SPARC between them.
The biopsy samples showed that the components of this pathway change together with human disease. Experiments in mice and cells allowed the authors to establish their order. In diabetic models, Klotho is the starting point of a pathway in which each component can be tested separately.