Mechanistic insights into the hepatoprotective activity of terminalia arjuna

Abstract

Non‐alcoholic fatty liver disease (NAFLD) affects roughly one quarter of the world’s population and is tightly associated with obesity and metabolic syndrome; despite its high prevalence, no fully effective pharmacotherapies have yet been approved. Terminalia arjuna, a traditional medicinal plant of the Combretaceae family, has long been used for both cardioprotective and hepatoprotective applications. In this study, we employed a systems‐biology framework, combining in silico transcriptomic profiling (RNA‐seq) with gene‐set and pathway enrichment analyses, to investigate three bioactive phytochemicals (Maslinic acid, ellagic acid, and plant‐derived sterols) from T. arjuna influence liver gene‐expression networks relevant to NAFLD. Our data corroborate previous findings that Maslinic acid suppresses key lipogenic transcription factors (including SREBP-1c and members of the C/EBP family) while enhancingthe expression of lipid‐catabolic and oxidative‐metabolism genes (such as PPAR-α and ATGL) through activation of the AMPK pathway, thereby reducing hepatic triglyceride levels and steatosis. Ellagic acid treatment signatures were marked by decreased oxidative stress and inflammatory markers (TNF-α, IL-6, ROS) alongside improved insulin sensitivity, whereas phytosterols exhibited the expected capacity to impede cholesterol uptake, diminish liver fat accumulation, and attenuate both oxidative injury and inflammatory signaling. Enrichment analyses further pinpointed modulation of several NAFLD‐related pathways, including fatty‐acid β-oxidation, cholesterol metabolism, cytokine‐mediated inflammation, and antioxidant defences. Taken together, our results suggest that these T. arjuna derived phytochemicals may act synergistically to re-establish metabolic homeostasis in the fatty liver, promoting lipid clearance and antioxidant responses while repressing de novo lipogenesis and inflammation. Overall, this work showcases the value of integrating network‐level transcriptomic analysis with ethnopharmacological knowledge, offering a versatile computational strategy for uncovering multi‐target mechanisms of hepatoprotection and guiding the development of plant‐based NAFLD therapeutics.