Kruppel-like Factors in Autophagy: A Spatiotemporal Rheostat Framework Linking Cellular Fate and Disease

Abstract Macroautophagy/autophagy links environmental cues to cellular adaptation, differentiation, and pathology. Krüppel-like factors (KLFs) influence autophagy across diverse contexts, yet their effects differ in direction and biological outcome, challenging a simple activation-versus-inhibition model. This perspective proposes a spatiotemporal rheostat framework for organizing KLF-autophagy interactions across cell-fate and disease contexts. It defines four experimentally testable dimensionsgraded modulation, temporal dependence, stage specificity, and reversibilityand evaluates representative studies using flux-aware evidence grading. Current evidence most strongly supports context- and stage-dependent KLF regulation, particularly through transcriptional control of early and intermediate autophagy components, whereas graded responses, temporal dynamics, and reversibility remain priorities for direct testing. Pharmacological analysis indicates that reported strategies rely mainly on upstream, pathway-level, or transcript-directed modulation, whereas direct KLF protein engagement remains unestablished. By reconciling heterogeneous evidence, the framework enables cross-context comparison and provides a basis for future mechanism-guided therapeutic investigation of the KLF-autophagy axis.