Autophagy-lysosome flux failure in diabetic kidney disease: tubular vulnerability and cell-state remodeling

Diabetic kidney disease (DKD) is conventionally framed as a glomerular microvascular complication but may also involve tubular degradative maladaptation, in which tubular cells progressively fail to clear damaged organelles, lipid droplets, and stress-related cargo through the autophagy-lysosome system. Among tubular compartments, proximal tubular epithelial cells depend particularly heavily on mitochondrial metabolism, endocytic trafficking, vesicular transport, and lysosome-supported proteostasis, making them especially vulnerable to diabetic metabolic stress. This review examines whether autophagy-lysosome failure, encompassing both initiation-level and flux-completion defects, provides a candidate link between adaptive tubular stress responses and maladaptive tubular cell-state remodeling. We appraise therapeutic opportunities for restoring degradative capacity, including standard metabolic and hemodynamic therapies, transcription factor EB (TFEB)- and AMP-activated protein kinase (AMPK)-centered interventions, selective autophagy modulation, and mechanism-guided integrative strategies. We propose a testable, stage-dependent reversibility framework, rather than an established DKD staging system: restoration of autophagy-lysosome flux and lysosomal capacity may be most effective before persistent senescence, ferroptotic vulnerability, and fibrosis become difficult to reverse. Accordingly, we distinguish initiation defects from completion defects using flux-competent criteria and identify the stage-dependent reversibility window as the principal conceptual contribution of this review, rather than a validated clinical staging construct.