Therapeutic and organelle contact-site modulation theory in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease affects roughly one third of adults worldwide and is expected to rise further. Despite its growing burden, effective pharmacological therapies remain limited. Emerging evidence indicates that disruption of communication between intracellular organelles, particularly between the endoplasmic reticulum and mitochondria, plays a central role in hepatic lipid accumulation, oxidative stress, and metabolic dysfunction. Restoration of these inter-organelle contact sites may therefore represent a unifying therapeutic strategy. This narrative review, guided by systematic search principles, examined published studies on selected medicinal herbs and their potential influence on organelle communication in non-alcoholic fatty liver disease. Six major databases were searched through December 2024. Twenty-eight in vivo, in vitro, and clinical studies met predefined inclusion criteria, focusing on seven botanicals widely used in traditional medicine. To complement thematic synthesis, abstracts were analyzed using computational text mining and network approaches to identify dominant mechanistic patterns. Across the literature, hepatic lipid metabolism and organelle stress emerged as central themes. Network analysis identified liver, lipid, and protein as highly connected concepts linking mechanistic and therapeutic domains. Topic modeling revealed four main research areas: phytochemical interventions, lipid droplet and organelle interface dynamics, metabolic profiling, and steatohepatitis models. Experimental findings indicate that several herbal compounds reduce steatosis, oxidative stress, and fibrosis while improving mitochondrial function and endoplasmic reticulum homeostasis. Lifestyle interventions such as aerobic exercise were also associated with improved lipid droplet and mitochondria interactions. However, most studies inferred modulation of organelle contact sites indirectly through downstream metabolic markers, and direct structural assessment remains limited. Current evidence suggests that modulation of inter-organelle contact sites may represent a convergent mechanism underlying the hepatoprotective effects of selected medicinal herbs. Enzymes involved in phospholipid remodeling and proteins governing organelle tethering appear as promising but underexplored therapeutic targets. Further mechanistic and multi-omics investigations, supported by well-designed clinical studies, are needed to translate these insights into effective treatments for non-alcoholic fatty liver disease.