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Phloretin is a natural dihydrochalcone found in many fruits and vegetables, especially in apple tree leaves and the Manchurian apricots, exhibiting several therapeutic properties, such as antioxidant, antidiabetic, anti-inflammatory, and antitumor activities. In this review article, the diverse aspects of the anticancer potential of phloretin are addressed, presenting its antiproliferative, proapoptotic, antimetastatic, and antiangiogenic activities in many different preclinical cancer models. The fact that phloretin is a planar lipophilic polyphenol and, thus, a membrane-disrupting Pan-Assay Interference compound (PAIN) compromises the validity of the cell-based anticancer activities. Phloretin significantly reduces membrane dipole potential and, therefore, is expected to be able to activate a number of cellular signaling pathways in a non-specific way. In this way, the effects of this minor flavonoid on Bax and Bcl-2 proteins, caspases and MMPs, cytokines, and inflammatory enzymes are all analyzed in the current review. Moreover, besides the anticancer activities exerted by phloretin alone, its co-effects with conventional anticancer drugs are also under discussion. Therefore, this review presents a thorough overview of the preclinical anticancer potential of phloretin, allowing one to take the next steps in the development of novel drug candidates and move on to clinical trials.

Acute kidney injury (AKI) is a global health concern with high incidence and mortality, where diabetes further worsens the condition. The available treatment options are not uniformly effective against the complex pathogenesis of AKI–diabetes comorbidity. Hence, combination therapies based on the multicomponent, multitarget approach can tackle more than one pathomechanism and can aid in AKI–diabetes comorbidity management. This study aimed to investigate the therapeutic potential of esculetin and phloretin combination against AKI–diabetes comorbidity by network pharmacology followed by validation by molecular docking and dynamics. The curative targets for diabetes, AKI, esculetin, and phloretin were obtained from DisGeNET, GeneCards, SwissTargetPrediction database. Further, the protein–protein interaction of the potential targets of esculetin and phloretin against AKI–diabetes comorbidity was investigated using the STRING database. Gene ontology and pathway enrichment analysis were performed with the help of the DAVID and KEGG databases, followed by network construction and analysis via Cytoscape. Molecular docking and dynamic simulations were performed to validate the targets of esculetin and phloretin against AKI–diabetes comorbidity. We obtained 6341 targets for AKI–diabetes comorbidity. Further, a total of 54 and 44 targets of esculetin and phloretin against AKI–diabetes comorbidity were retrieved. The top 10 targets for esculetin selected based on the degree value were AKR1B1, DAO, ESR1, PLK1, CA3, CA2, CCNE1, PRKN, HDAC2, and MAOA. Similarly, phloretin’s 10 key targets were ACHE, CDK1, MAPK14, APP, CDK5R1, CCNE1, MAOA, MAOB, HDAC6, and PRKN. These targets were enriched in 58 pathways involved in the pathophysiology of AKI–diabetes comorbidity. Further, esculetin and phloretin showed an excellent binding affinity for these critical targets. The findings of this study suggest that esculetin and phloretin combination as a multicomponent multitarget therapy has the potential to prevent AKI–diabetes comorbidity. Graphical abstract

During age-related macular degeneration (AMD), chronic inflammatory processes, possibly fueled by high glucose levels, cause a breakdown of the retinal pigment epithelium (RPE), leading to vision loss. Phloretin, a natural dihydroxychalcone found in apples, targets several anti-inflammatory signaling pathways and effectively inhibits transporter-mediated glucose uptake. It could potentially prevent inflammation and cell death of RPE cells through either direct regulation of inflammatory signaling pathways or through amelioration of high glucose levels. To test this hypothesis, ARPE-19 cells were incubated with or without phloretin for 1 h before exposure to lipopolysaccharide (LPS). Cell viability and the release of pro-inflammatory cytokines interleukin 6 (IL-6), IL-8 and vascular endothelial growth factor (VEGF) were measured. Glucose uptake was studied using isotope uptake studies. The nuclear levels of nuclear factor erythroid 2-related factor 2 (Nrf2) were determined alongside the phosphorylation levels of mitogen-activated protein kinases. Phloretin pretreatment reduced the LPS-induced release of IL-6 and IL-8 as well as VEGF. Phloretin increased intracellular levels of reactive oxygen species and nuclear translocation of Nrf2. It also inhibited glucose uptake into ARPE-19 cells and the phosphorylation of Jun-activated kinase (JNK). Subsequent studies revealed that Nrf2, but not the inhibition of glucose uptake or JNK phosphorylation, was the main pathway of phloretin’s anti-inflammatory activities. Phloretin was robustly anti-inflammatory in RPE cells and reduced IL-8 secretion via activation of Nrf2 but the evaluation of its potential in the treatment or prevention of AMD requires further studies.

Toll-like receptor 2 (TLR2) responses are involved in various inflammatory immune disorders. Phloretin is a naturally occurring dietary flavonoid that is abundant in fruit. Here, we investigated whether the anti-inflammatory activity of phloretin is mediated through TLR2 pathways, and whether phloretin acts as an inhibitor of TLR2/1 heterodimerization using the TLR2/1 agonist Pam3CSK4. We tested the effects of phloretin on tumor necrosis factor (TNF)-α production induced by various TLRs using known TLR-specific agonists. Phloretin significantly inhibited Pam3CSK4-induced TRL2/1 signaling in Raw264.7 cells compared to TLR signaling induced by the other agonists tested. Therefore, we further tested the effects of phloretin in human embryonic kidney (HEK) 293-hTLR2 cells induced by Pam3CSK4, and confirmed that phloretin has comparable inhibition of TLR2/1 heterodimerization to that induced by the known TLR2 inhibitor CU-CPT22. Moreover, phloretin reduced the secretion of the inflammatory cytokines TNF-α and interleukin (IL)-8 in Pam3CSK4-induced HEK293-hTLR2 cells, whereas it did not significantly reduce these cytokines under Pam2CSK4-induced activation. Western blot results showed that phloretin significantly suppressed Pam3CSK4-induced TLR2 and NF-κB p65 expression. The molecular interactions between phloretin and TLR2 were investigated using bio-layer interferometry and in silico docking. Phloretin bound to TLR2 with micromolar binding affinity, and we proposed a binding model of phloretin at the TLR2–TLR1 interface. Overall, we confirmed that phloretin inhibits the heterodimerization of TLR2/1, highlighting TLR2 signaling as a therapeutic target for treating TLR2-mediated inflammatory immune diseases.

Subarachnoid hemorrhage (SAH), a stroke subtype associated with high mortality, is closely linked to neuroinflammation. Phloretin, a naturally occurring flavonoid abundant in fruits, possesses anti-inflammatory properties. However, its specific role in SAH remains unclear. Therefore, we aimed to investigate the potential role of phloretin in SAH. We established in vitro and in vivo SAH models to assess the effects of phloretin. Subsequently, utilizing SAH-related public datasets from the GEO database, we identified key genes associated with SAH and investigated the potential mechanism of action of phloretin. Our findings reveal that phloretin significantly improves prognostic outcomes and mitigates inflammation in SAH mice. Moreover, our results suggest that phloretin mitigates neuroinflammation by inhibiting the TLR2/MYD88/NF-κB pathway.

The phenolic compound phloretin is a prominent member of the chemical class of dihydrochalcones. Phloretin is specifically found in apple and apple juice and known for its biological properties. We were particularly interested in its potential dermo-cosmetic applications. However, practical limitations of phloretin do exist due to its poor water-solubility. Phloretin was sulfonated with sulfuric acid (98%, wt) and mixed with saturated salt water to produce phloretin 3',3-disulfonate in order to increase its water-solubility. Here we reported the photoprotective effect of phloretin 3',3-disulfonate (PS), a new semi-synthetic derivative of phloretin. Results showed that PS attenuated cyclobutane pyrimidine dimer (CPDs) formation, glutathione (GSH) depletion and apoptosis induced by ultraviolet B (UVB). The photoprotective effect of PS is tightly correlated to the enhancement of nucleotide excision repair (NER) gene expression. Furthemore, PS had inhibitory effects on UVB-induced release of the inflammatory mediators, such as IL-6 and prostaglandin-E2. We also confirmed the safety and clinical efficacy of PS on human skin. Overall, the results demonstrated significant benefits of PS on the protection of keratinocytes against UVB-induced injuries and suggested its potential use in skin photoprotection.

Plant-derived food consumption has gained attention as potential intervention for the improvement of intestinal inflammatory diseases. Apple consumption has been shown to be effective at ameliorating intestinal inflammation symptoms. These beneficial effects have been related to (poly)phenols, including phloretin (Phlor) and its glycoside named phloridzin (Phldz). To deepen the modulatory effects of these molecules we studied: i) their influence on the synthesis of proinflammatory molecules (PGE2, IL-8, IL-6, MCP-1, and ICAM-1) in IL-1β-treated myofibroblasts of the colon CCD-18Co cell line, and ii) the inhibitory potential of the formation of advanced glycation end products (AGEs). The results showed that Phlor (10–50 μM) decreased the synthesis of PGE2 and IL-8 and the formation of AGEs by different mechanisms. It is concluded that Phlor and Phldz, compounds found exclusively in apples, are positively associated with potential beneficial effects of apple consumption.

Background Macrophages play a dual role in neuroinflammatory disorders such as multiple sclerosis (MS). They are involved in lesion onset and progression but can also promote the resolution of inflammation and repair of damaged tissue. In this study, we investigate if and how phloretin, a flavonoid abundantly present in apples and strawberries, lowers the inflammatory phenotype of macrophages and suppresses neuroinflammation. Methods Transcriptional changes in mouse bone marrow-derived macrophages upon phloretin exposure were assessed by bulk RNA sequencing. Underlying pathways related to inflammation, oxidative stress response and autophagy were validated by quantitative PCR, fluorescent and absorbance assays, nuclear factor erythroid 2–related factor 2 (Nrf2) knockout mice, western blot, and immunofluorescence. The experimental autoimmune encephalomyelitis (EAE) model was used to study the impact of phloretin on neuroinflammation in vivo and confirm underlying mechanisms. Results We show that phloretin reduces the inflammatory phenotype of macrophages and markedly suppresses neuroinflammation in EAE. Phloretin mediates its effect by activating the Nrf2 signaling pathway. Nrf2 activation was attributed to 5′ AMP-activated protein kinase (AMPK)-dependent activation of autophagy and subsequent kelch-like ECH-associated protein 1 (Keap1) degradation. Conclusions This study opens future perspectives for phloretin as a therapeutic strategy for neuroinflammatory disorders such as MS. Trial registration Not applicable.

Colorectal carcinoma (CRC) is the third most prevalent cancer, causing a significant mortality worldwide. Present available therapies are surgery, chemotherapy including radiotherapy, and these are known to be associated with heavy side effects. Therefore, nutritional intervention in the form of natural polyphenols has been well recognised to prevent CRC. Phloretin, a known dihydrochalcone is present in apple, pear and strawberry. This has been proven to induce apoptosis in cancer cells and also exhibited anti-inflammatory activity, thus can be explored as a potential anticancer nutraceutical agent. This study demonstrated phloretin’s significant in vitro anticancer activity against CRC. Phloretin suppressed cell proliferation, colony forming ability and cellular migration in human colorectal cancer HCT-116 and SW-480 cells. Results also revealed that phloretin generated reactive oxygen species (ROS) which provoked depolarization of mitochondrial membrane potential (MMP) and further contributed to cytotoxicity in colon cancer cells. Phloretin also modulated the cell cycle regulators including cyclins and cyclin-dependent kinases (CDKs) and halted cell cycle at G2/M phase. Moreover, it also induced apoptosis by regulating the expression of Bax and BCl-2. The Wnt/β-catenin signaling is inactivated by phloretin by targeting the downstream oncogenes namely CyclinD1, c-Myc and Survivin which are involved in the proliferation and apoptosis of colon cancer cells. In our study we showed that lithium chloride (LiCl) induced the expression of β-catenin and its target genes and the co-treatment of phloretin circumvent its effect and downregulated the Wnt/β-catenin signaling. In conclusion, our results strongly suggested that phloretin can be utilized as a nutraceutical anticancer agent for combating CRC.

Phloretin is a natural chalcone with antibacterial and anti-inflammatory effects. This study investigated the anti-acne activity of phloretin against Propionibacterium acnes-induced skin infection and the potential target proteins of its anti-inflammatory and antibacterial effects. Phloretin potently inhibited the growth of P. acnes and P. acnes-induced Toll-like receptor (TLR) 2-mediated inflammatory signaling in human keratinocytes. Secreted embryonic alkaline phosphatase assay confirmed that the anti-inflammatory activity of phloretin is associated with the P. acnes-stimulated TLR2-mediated NF-κB signaling pathway. Phloretin significantly decreased the level of phosphorylated c-Jun N-terminal kinase (JNK), showing a binding affinity of 1.184 × 10−5 M−1. We also found that phloretin binds with micromolar affinity to P. acnes β-ketoacyl acyl carrier protein (ACP) synthase III (KAS III), an enzyme involved in fatty acid synthesis. Conformation-sensitive native polyacrylamide gel electrophoresis showed that phloretin reduced KAS III-mediated 3-ketoacyl ACP production by over 66%. A docking study revealed that phloretin interacts with the active sites of JNK1 and KAS III, suggesting their involvement in P. acnes-induced inflammation and their potential as targets for the antibacterial activity of phloretin. These results demonstrate that phloretin may be useful in the prevention or treatment of P. acnes infection.