Lysosomal dysfunction in septic acute kidney injury: Molecular mechanisms and disease progression

Septic acute kidney injury (AKI) remains a major cause of morbidity and mortality in critically ill patients, and renal dysfunction often persists despite restoration of systemic hemodynamics. This dissociation suggests that septic AKI is driven not only by impaired perfusion but also by sustained tubular metabolic stress. Emerging evidence identifies lysosomes as important regulators of this process in renal tubular epithelial cells. In this review, we discuss how vacuolar H⁺-ATPase (V-ATPase) disassembly links mitochondrial dysfunction and NAD+ depletion to loss of lysosomal acidification and impaired anabolic recovery; how defective lysosome-dependent mitochondrial and lipid quality control promotes lipotoxicity and ferroptosis; how lysosomal exocytosis reshapes immune crosstalk through extracellular vesicle signaling; and how NINJ1-mediated plasma membrane rupture may amplify local tubular necrosis into microvascular dysfunction and immunothrombosis. Together, these mechanisms provide a molecular framework for understanding how lysosomal dysfunction contributes to the progression of septic AKI from adaptive stress responses to irreversible injury, and they highlight potential stage-specific therapeutic strategies.