Natural Modulators of Aquaporins in Cancer Therapy: Functional Mechanisms and Clinical Potential.

Aquaporins (AQPs) are increasingly recognized as key regulators of tumor progression, influencing key hallmarks of cancer progression and cellular homeostasis. Their frequent overexpression in malignancies highlights their potential as therapeutic targets, yet the development of selective synthetic inhibitors remains challenging due to structural conservation and off-target toxicity. Natural compounds have recently emerged as promising modulators of AQP expression and function, offering greater molecular diversity and generally favorable safety profiles. This review synthesizes current evidence on phytochemicals, including bacopaside II, curcumin, resveratrol, quercetin, EGCG, all-trans retinoic acid, chrysin, and rottlerin, that interact with AQP isoforms relevant to cancer biology. These agents regulate AQPs through transcriptional control, redox modulation, signaling-pathway interference, or direct pore blockade, thereby attenuating oncogenic processes such as migration, angiogenesis, inflammation, and metabolic adaptation. Several compounds, notably bacopaside II and rottlerin, display isoform-selective inhibitory properties that directly impair AQP1- and AQP3-mediated permeability. Collectively, available evidence positions natural AQP modulators as promising lead compounds providing scaffolds for further drug development in oncology. Continued structural, mechanistic, and preclinical research is required to optimize isoform specificity and therapeutic efficacy, paving the way for their integration into future anticancer strategies.