A recent study documented a novel role for the transcription factor RUNX1 in driving inflammation in acute kidney injury, suggesting a potential pathway for new therapies in this often fatal condition.

Acute kidney injury (AKI) is a sudden decline in kidney function, with severe cases leading to chronic kidney disease (CKD) and a mortality rate up to 50%. Although treatments for AKI are limited, this study presents evidence that RUNX1 upregulation is a critical factor in driving inflammation in AKI, leading to greater tissue damage. RUNX1 is already known for its regulatory role in blood cell development and has been implicated in several cancers, but this is the first study to uncover its involvement in AKI.

In the study, published in The Journal of Pathology, researchers found inhibiting RUNX1 activity significantly improved kidney function and reduced inflammation in mouse models of AKI, marking a breakthrough in understanding AKI pathogenesis.

Using a chemical inhibitor of RUNX1, Ro5-3335, the researchers tested its efficacy in two mouse models of AKI—one induced by folic acid (FA-AKI) and the other by a bacterial toxin lipopolysaccharide (CS-AKI). RUNX1 levels were found to spike within hours of AKI onset, localized predominantly in kidney tubule cells, where it bound to proinflammatory genes, particularly interleukin (IL)-6. RUNX1-driven IL-6 expression was identified as a main contributor to the inflammatory response, while other inflammatory genes were RUNX1-independent.

Inhibiting RUNX1 with Ro5-3335 before AKI onset in mice showed a marked improvement in kidney function, reducing both inflammation and cell death. Interestingly, while RUNX1 inhibition helped prevent both FA-AKI and CS-AKI, therapeutic benefits differed depending on the timing and model. In CS-AKI, administration of the inhibitor even after injury improved kidney outcomes, while only preventive administration was effective in FA-AKI.

Transcriptomic analyses of injured kidney tissues showed Ro5-3335 not only lowered IL-6 but also reduced other inflammatory mediators, including several transcription factors linked to kidney damage, such as NFκB, YAP1, and p53. This effect revealed a complex network regulated by RUNX1, in which inflammation and fibrosis were capable of accelerating the transition from AKI to CKD. The findings indicated that targeted RUNX1 inhibition could disrupt this harmful cascade, potentially preventing long-term kidney damage.

The clinical relevance of these findings was underscored by observations of elevated RUNX1 levels in kidney tissues from patients with AKI, suggesting that RUNX1-targeted therapies may benefit human patients as well. However, because RUNX1 inhibitors like Ro5-3335 are still in the experimental phase, further studies are needed to refine dosing, timing, and specificity for AKI.

This study positions RUNX1 as a central mediator of kidney injury and highlights its potential as a therapeutic target to mitigate inflammation and kidney damage in AKI.