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. 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.