Natural Plant-Derived Compounds Targeting Oxidative Stress and Inflammation in NAFLD—Mechanisms and Repositioning Potential

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, with advanced stages potentially progressing to hepatocellular carcinoma. It is a multifactorial condition associated with metabolic syndrome, diabetes, and hormonal imbalance, leading to metabolic alterations that are intensified by inflammation. An important additional factor that amplifies these effects is oxidative stress, which interacts with inflammatory pathways and contributes to disease progression. This review evaluates evidence from in vitro, in vivo, and clinical studies on widely investigated natural compounds, including cinnamic acid, stilbene and quinone derivatives, coumarinoids, tannins, and miscellaneous phenol-containing compounds and alkaloids, focusing on their antioxidant, anti-inflammatory and multi-functional properties. These compounds have demonstrated beneficial effects such as reduction of lipid accumulation, improvement of insulin resistance, modulation of inflammatory cytokines (e.g., TNF-α, IL-6), and attenuation of oxidative stress markers, with several studies reporting improvements in liver enzymes and histological features of steatosis. The aim is to assess their potential to improve NAFLD beyond their established biological activities and to explore their repositioning potential as multi-targeted agents for complementary or second-line therapeutic strategies. Their plant-derived origin and broad therapeutic profiles suggest a favorable safety margin. However, further well-designed clinical studies are required to better define their efficacy, optimal dosing, pharmacokinetics and safety, as well as to clarify their mechanisms of action and their potential role in NAFLD management.