Bio-active compounds and extracellular vesicles modulate stress responses in liver cells

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health burden characterized by hepatic lipid accumulation, progressing to inflammation, fibrosis, and hepatocellular carcinoma. This thesis investigates the therapeutic potential of bioactive compounds and extracellular vesicles (EVs) in modulating stress responses underlying MASLD pathogenesis. Using in vitro models of lipotoxicity and hepatic stellate cell (HSC) activation, we demonstrate that the coumarin derivative esculetin attenuates palmitate-induced oxidative stress and necrosis in hepatocytes. This effect occurs through the suppression of JNK activation and the enhancement of Nrf2-mediated antioxidant defense. Additionally, esculetin decreases lipid accumulation by downregulating lipogenesis through AMPKα and promoting fatty acid oxidation via Ppar-α. In HSCs, the lignan arctigenin inhibits ER stress-induced activation by restoring lipid droplet homeostasis. Arctigenin suppresses ER-associated degradation (ERAD), downregulates Pnpla2-mediated lipolysis, and enhances lipogenesis (Dgat2, Ppar-γ), thereby attenuating fibrogenic markers (α-SMA, collagen-I). Furthermore, inhibition of GSK-3β promotes collagen-I production in HSCs by impairing autophagic flux through mTORC1 signaling, highlighting its role in fibrogenesis. Finally, EVs from steatotic hepatocytes induce HSC senescence via AKT/mTOR pathways, revealing their dual role in disease progression. Collectively, these findings underscore the efficacy of natural compounds in targeting lipotoxicity, ER stress, and fibrogenic pathways, while EVs emerge as critical mediators of hepatocyte-HSC crosstalk. This work provides novel insights into therapeutic strategies for MASLD, highlighting the promise of bio-active compounds and EV-based interventions in managing hepatic stress responses and fibrosis.