Journal of medicinal chemistryOct 23, 2026

Krüppel-like Factors as Timed Regulators of Cell Recycling That Influence Cell Survival and Disease

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 24, 2026

Abstract

KLF regulation of autophagy is context- and stage-dependent.

Krüppel-like factors (KLFs) influence autophagy in various biological contexts, with effects that can differ in direction and outcome.
A proposed spatiotemporal rheostat framework organizes KLF-autophagy interactions based on graded modulation, temporal dependence, stage specificity, and reversibility.
Current evidence supports that KLFs regulate early and intermediate components of autophagy primarily through transcriptional control.
Graded responses, temporal dynamics, and reversibility of KLF effects on autophagy are identified as areas for future investigation.
Pharmacological strategies currently focus on upstream modulation rather than direct engagement with KLF proteins.

Simplified

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.

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Krüppel-like Factors as Timed Regulators of Cell Recycling That Influence Cell Survival and Disease

Abstract

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