Phloridzin as a Nutraceutical for Cancer Prevention and Therapy: A Comprehensive Review of Its Mechanisms, Bioavailability Challenges and Future Applications

Abstract

The global rise in cancer incidence has driven the search for safer, more effective therapies, with natural compounds gaining increasing attention. Phloridzin, a dihydrochalcone glycoside abundant in apple trees (Malus spp.), has demonstrated notable anticancer properties. This review summarizes its pharmacological profile, natural sources, and structural characteristics, with a focus on its mechanisms of antitumor action. We conducted a structured literature search across SCOPUS, PubMed, Google Scholar, and TRIP databases, highlighting studies on phloridzin's anti-proliferative, pro-apoptotic, anti-inflammatory, and metabolic regulatory effects across various in vitro and in vivo cancer models. Key mechanisms include glucose transporter inhibition (GLUT1/2), modulation of PI3K/AKT/mTOR and JAK2/STAT3 signaling, and suppression of metastasis and angiogenesis. Despite compelling preclinical evidence, phloridzin's clinical application is limited by low bioavailability. Novel delivery systems and synthetic derivatives, such as fatty acid esters, have shown improved pharmacokinetic profiles and efficacy. Future studies should prioritize translational research and clinical trials to validate phloridzin's potential as an adjunct or alternative therapy in oncology.

Keywords: GLUT inhibitors; anticancer activity; bioavailability; flavonoids; phloridzin.

FIGURE 1

Chemical structure of phloridzin.

FIGURE 2

Biosynthetic pathway of phloridzin.

FIGURE 3

Molecular mechanisms of phloridzin's antitumor activity, highlighting its role in apoptosis induction, metastasis suppression, and angiogenesis inhibition. Phloridzin inhibits JAK2/STAT3 signaling, preventing STAT3 phosphorylation and nuclear translocation, which downregulates Bcl‐2 expression and promotes apoptosis via the Akt/mTOR pathway. Additionally, phloridzin suppresses HIF‐1α‐mediated VEGF expression, thereby inhibiting tumor angiogenesis. The compound also inhibits pro‐matrix metalloproteinases (pro‐MMPs) activation, reducing the expression of key metastatic proteins (CD31, FAK, Fibronectin, MAP kinases, NF‐κB, and Rho A), leading to antimetastatic effects. Moreover, phloridzin enhances TRAIL/TNFα‐induced apoptosis, activating the caspase‐8 and caspase‐3 cascade. Akt, Protein kinase B; Bcl‐2, Anti‐apoptotic protein; CD31, Endothelial adhesion molecule; Casp‐3, Executioner caspase in apoptosis; Casp‐8, Initiator caspase in apoptosis; FAK, Focal adhesion kinase; Fibronectin, Cell adhesion glycoprotein; GLUT, Glucose transporter; HIF‐1α, Hypoxia‐inducible factor‐1 alpha; JAK2, Janus kinase 2; MAPK, Mitogen‐activated protein kinase; MMPs, Matrix metalloproteinases; NF‐κB, Nuclear factor kappa B; P‐Phlor, Phloridzin; Pro‐Casp‐3, Inactive caspase‐3 precursor; Pro‐Casp‐8, Inactive caspase‐8 precursor; Pro‐MMPs, Inactive metalloproteinases; Rho A, GTPase regulating migration; STAT3, Signal transducer and activator of transcription 3; TNFα, Tumor necrosis factor‐alpha; TRAIL, TNF‐related apoptosis‐inducing ligand; VEGF, Vascular endothelial growth factor.