Dietary Flavonoid Phloretin and Its Synthetic Derivative Inhibit Platelet Activation and Thrombosis via the SRC/PI3K/Akt Signaling Pathway

Abstract Thrombotic diseases are a leading cause of global mortality, primarily driven by pathological platelet activation. Phloretin, a natural flavonoid abundant in apple peels with anti-inflammatory and antioxidant properties, is limited by poor solubility and bioavailability. To overcome these limitations, a synthetic derivative was designed and evaluated for antiplatelet and antithrombotic effects. Phloretin and its derivative inhibited platelet aggregation, ATP release, and integrin αIIbβ3 activation in vitro. In vivo, administration at 12.5 mg/kg significantly delayed thrombus formation without affecting bleeding time. Pharmacokinetic analysis showed that the methylated derivative exhibited enhanced bioavailability compared to phloretin. Network pharmacology, molecular docking, and molecular dynamics identified SRC and Akt1 as key targets with stable interactions. Western blotting confirmed inhibition of the SRC/PI3K/Akt/PKC signaling pathway. These findings establish phloretin, a food-derived flavonoid from apple peels, and its bioavailability-optimized derivative as multitarget antiplatelet candidates targeting the SRC/PI3K/Akt/PKC axis, highlighting their potential for cardiovascular protection.