From molecular chaos to precision medicine in the treatment of cardiac hypertrophy: A rational use of natural products by integrating artificial intelligence and multi-omics data.

Given the intricate and multifactorial molecular mechanisms underlying cardiac hypertrophy (CH), conventional pharmacological treatments often face significant challenges in achieving disease reversal. This review presents an innovative approach to treating CH by combining natural products with artificial intelligence (AI) and multi-omics technologies. We provide detailed analysis of the molecular pathways that drive pathological hypertrophy, with a particular emphasis on impaired calcium signaling and the pro-inflammatory-oxidative feedback loop involving ferroptosis and pyroptosis. Advanced AI-driven methodologies, such as single-cell spatial transcriptomics and machine learning algorithms, facilitate a more nuanced understanding of cellular heterogeneity and the identification of key pharmacological targets, including Sirtuin 3 (SIRT3) and Toll-Like Receptor 4 (TLR4). Natural products like ginsenoside Rb1 and baicalin exhibit superior multitarget pharmacological effects compared to conventional single-target drugs, effectively modulating critical pathways like AMP-activated protein kinase (AMPK) activation and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibition. Moreover, metabolites derived from the gut microbiota, including trimethylamine N-oxide (TMAO) and short-chain fatty acids, emerge as novel modulators of cardiac remodeling, influencing epigenetic regulation through pathways such as the Histone Deacetylases (HDACs)-PHD Finger Protein 21B (PHF21B) axis. By integrating cutting-edge technologies with pharmacological insights, this review outlines a comprehensive strategy for precision pharmacotherapy, ranging from early-stage signaling modulation to systemic network reprogramming, thus shifting the focus of treatment from symptom management to potential disease reversal.