Investigating the Therapeutic Effects of Naringenin and Oleuropein on Prostate Cancer Cell Mat-LyLu via miR-155-5p: A Bioinformatics and Molecular Docking Analysis of KRAS and CDK2 Networks

<b>Background:</b> This study systematically investigates the therapeutic effects of naringenin (NAR) and oleuropein (OLE) on prostate cancer through miR-155-5p regulation. <b>Methods:</b> Experimental studies conducted on MAT-LyLu prostate cancer cell lines revealed that the application of NAR (50 μM) and OLE (75 μM) significantly increased miR-155-5p expression by 2.89-fold and 1.74-fold, respectively (<i>p</i> < 0.05). Bioinformatics analyses have indicated that miR-155-5p interacts with critical oncogenic pathways such as <i>KRAS</i>, <i>CDK2</i>, NF-κB, and TGF-β/Smad2. Computational analyses have revealed that miR-155-5p interacts with 16 critical oncogenic targets, including <i>KRAS</i> and <i>CDK2.</i> Molecular docking studies showed that NAR binds to the Switch I/II region of <i>KRAS</i> with a binding energy of -8.2 kcal/mol, while OLE binds to the ATP-binding pocket of <i>CDK2</i> with an affinity of -9.1 kcal/mol. Pharmacokinetic evaluations revealed that NAR indicated high oral bioavailability (93.763% HIA) and full compliance with Lipinski's rules, while OLE required advanced formulation strategies due to its high polarity. Network pharmacology analyses have shown that NAR affects lysosomal functions and enzyme regulation, while OLE affects G protein-coupled receptors and oxidoreductase activity. <b>Results</b>: Results indicate that NAR and OLE exhibit antitumor effects through multiple mechanisms by increasing miR-155-5p expression and inhibiting critical oncogenic targets in prostate cancer. <b>Conclusions:</b> Findings suggest that the dietary intake of these natural compounds (citrus and olive products) should be considered in prostate cancer prevention strategies, shedding light on the epigenetic mechanisms of polyphenols in cancer treatment and contributing to the development of new therapeutic strategies.