Mechanism Exploration of Dietary Supplement Astaxanthin on Improving Atherosclerosis through an Integrated Strategy Encompassing Artificial Intelligence Virtual Screening and Experimental Validation

Abstract

Atherosclerosis (AS) is a major and common pathological basis of ischemic intestinal infarction, myocardial infarction, stroke, renal failure, and other highly lethal and disabling diseases. Current pharmacological interventions (e.g., statins) often cause adverse effects, limiting their long-term use. Natural compounds, with their multitarget efficacy and superior safety profiles, have emerged as promising alternatives for AS treatment. As a potent antioxidant carotenoid, astaxanthin exhibits unique therapeutic potential by simultaneously targeting inflammation, oxidative stress, and lipid metabolism, which are key drivers of AS pathogenesis. This study will systematically decipher astaxanthin’s therapeutic mechanisms through an integrative strategy encompassing artificial intelligence virtual screening and experimental validation. Notably, five proteins, including CTSD, DPP4, FABP5, ITGAL, and MMP9, were identified as core targets for astaxanthin intervention in AS via network pharmacology and machine learning. Meanwhile, the results from molecular dynamic simulations confirmed that these core targets can stable binding with astaxanthin. Furthermore, in vitro experiments further validated astaxanthin can inhibit foam cell formation, restore redox balance, and suppress inflammation. Moreover, a close correlation has been found between them. These findings position astaxanthin as a multitarget natural agent to combat AS, addressing both efficacy advantage and safety concerns of current therapies.