Discovery Pipeline for AKI: Molecules, Mechanisms, Models, and Targets

Background: Acute kidney injury (AKI) represents a multifaceted clinical syndrome marked by precipitous loss of kidney function, high morbidity and mortality, and a strong propensity for progression to chronic kidney disease. Collectively, these challenges underscore the imperative to delineate conserved molecular and signaling networks that are uniformly engaged across diverse AKI etiologies. Summary: Herein, we survey five emerging research domains poised to transform AKI pathophysiology and therapeutic paradigms. First, lymphatic network remodeling has been implicated as a critical determinant of renal immunodynamics and interstitial fluid homeostasis, whereby modulation of VEGF-C/D signaling reshapes immune cell trafficking and fibrogenic responses. Second, we will cover emerging evidence that positions macrophage ferritin heavy chain as a key regulator of macrophage phenotype and subsequent kidney ferroptosis susceptibility via coordinated regulation of synuclein-⍺, and Spic. Third, we will emphasize incorporating development as a biological variable into experimental design based on evidence that identifies age‐dependent divergences in injury susceptibility, and progression of disease. Fourth, we cover mechanosensitive ion channels that are activated by therapeutic ultrasound offering novel opportunities to harness the cholinergic anti-inflammatory pathway for nephroprotection. Finally, targeting tubular epithelial cell senescence and mitochondrial bioenergetics as a promising approach to limit progression of kidney disease will be discussed. Key Messages: Collectively, these emerging mechanisms deepen our understanding of AKI pathophysiology and unveil novel therapeutic targets with the potential to transform the treatment landscape.