Abstract
Hydroxytyrosol (HT), a principal bioactive phytochemical abundant in Mediterranean dietary sources, has emerged as a molecule of significant scientific interest owing to its multifaceted health-promoting properties. Accumulating evidence suggests that HT's therapeutic potential in metabolic disorders extends beyond conventional antioxidant capacity to encompass mitochondrial regulatory networks. This review synthesizes contemporary evidence from our systematic investigations and the existing literature to delineate HT's comprehensive modulatory effects on mitochondrial homeostasis. We systematically summarized the impact of HT on mitochondrial dynamics (fusion/fission equilibrium), biogenesis and energy metabolism, mitophagy, inter-organellar communication with the endoplasmic reticulum, and microbiota-mitochondria crosstalk. Through this multidimensional analysis, we established HT as a mitochondrial homeostasis modulator with potential therapeutic applications in metabolic syndrome (MetS) and its related pathologies including type 2 diabetes mellitus, obesity-related metabolic dysfunction, dyslipidemia, non-alcoholic steatohepatitis, and hypertension-related complications. Moreover, we further discussed translational challenges in HT research, emphasizing the imperative for direct target identification, mitochondrial-targeted delivery system development, and combinatorial therapeutic strategies. Collectively, this review provides a mechanistic framework for advancing HT research and accelerating its clinical implementation in MetS and its related diseases.