Molecular Mechanisms of the Anticancer Activity of the Flavonoid Kaempferol: A Comprehensive Review.

Abstract

Kaempferol (KAE), a natural flavonoid, has emerged as a promising multi-target antineoplastic agent characterized by high efficacy and minimal systemic toxicity. Moving beyond fragmented descriptive summaries, this comprehensive review provides a highly integrated conceptual framework of KAE's anticancer mechanisms. Specifically, KAE orchestrates tumor eradication by enforcing cell cycle arrest across multiple phases and triggering a complex, interconnected network of programmed cell death. We highlight how reactive oxygen species and endoplasmic reticulum stress serve as central upstream nodes driving the mechanistic crosstalk among apoptosis, lethal autophagy, gasdermin E-mediated pyroptosis, and ferroptosis. Furthermore, KAE actively remodels the tumor microenvironment by inhibiting angiogenesis and repolarizing tumor-associated macrophages, thereby converting immunosuppressive "cold" tumors into immune-active "hot" tumors. Notably, this review introduces the emerging prebiotic-like crosstalk between KAE and the gut microbiome, providing a strong mechanistic rationale for its synergistic application with immune checkpoint inhibitors. As a potent chemosensitizer, KAE also overcomes multidrug resistance and mitigates chemotherapy-induced toxicities. Finally, we critically evaluate current translational bottlenecks-including the disparity between supraphysiological in vitro concentrations and clinical pharmacokinetics, the lack of robust in vivo validations, and the long-term biosafety of emerging nano-delivery systems. By addressing these critical limitations, this review offers strategic perspectives to bridge the gap from preliminary bench research to future precision oncological practice.