Mechanistic Insights into the Effects of Carnosic Acid on the Liver.

Carnosic acid (CA), a phenolic diterpene abundant in Rosmarinus officinalis, has emerged as a bioactive compound with multifaceted effects on hepatic cells and liver tissue. The present work aims to critically discuss, from a mechanistic perspective, the molecular and cellular effects induced by CA on the liver, integrating evidence from in vitro and in vivo experimental models. Across hepatocytes, hepatic stellate cells, and hepatocellular carcinoma models, CA consistently modulates redox balance, inflammatory signaling, mitochondrial integrity, metabolic pathways, and cell fate decisions. Mechanistically, CA engages signaling hubs such as Nrf2, SIRT1, AMPK, p66Shc, NF-κB, and Akt/mTOR, thereby coordinating antioxidant defenses, suppression of inflammation, regulation of lipid and glucose metabolism, and control of apoptosis and autophagy. Importantly, these effects are highly context-dependent, with CA promoting cytoprotection and metabolic homeostasis in non-transformed hepatic cells, while inducing apoptotic or autophagy-related cell death in hepatocellular carcinoma models. Despite this robust mechanistic framework, significant gaps remain regarding CA bioavailability, intracellular distribution, mitochondrial targeting, and the integration of metabolic reprogramming with redox and inflammatory signaling. Collectively, the data position CA as a pleiotropic modulator of hepatic biology and highlight its translational potential, while underscoring the need for more refined mechanistic and pharmacokinetic investigations.