Dose-dependent tuning of HSP70-Beclin-1 by kaempferol governs autophagy and chemosensitivity.

INTRODUCTION

Autophagy can either support cell survival or promote cell death in response to therapeutic stress, yet the molecular switch that determines this directionality remains poorly defined.

METHODS

Using kaempferol as a proof‑of‑concept flavonoid and esophageal squamous carcinoma cells as a model system, we investigated its dose‑dependent effects on the HSP70-Beclin‑1 complex. In vivo experiments were also performed to evaluate kaempferol's modulation of cisplatin's antitumor activity.

RESULTS

Low‑dose kaempferol stabilized the HSP70-Beclin‑1 association, suppressed autophagic flux, and attenuated chemotherapy‑induced apoptosis. In contrast, high‑dose kaempferol disrupted this complex and enhanced autophagic flux through coordinated activation of AMPK/mTOR inhibition and ER stress-JNK signaling, leading to robust autophagy‑dependent chemosensitization. In vivo, high‑dose kaempferol potentiated cisplatin's antitumor activity, whereas low‑dose kaempferol diminished it.

DISCUSSION: These findings reveal a generalizable molecular logic in which dose‑dependent modulation of a chaperone-autophagy initiation complex governs autophagy directionality and therapeutic response. By elucidating how a single compound can toggle this central regulatory node, the study provides a conceptual framework for optimizing the dosing of natural products and for leveraging autophagy‑based chemosensitization strategies across diverse tumor contexts.