As the global burden of metabolic disease accelerates, the pharmaceutical pipeline for fatty liver disease remains frustratingly narrow — one approved drug for MASH, and GLP-1 agonists that carry meaningful tolerability trade-offs. A major review in Pharmacological Reviews now maps the molecular terrain where natural compounds may fill that gap, cataloging direct protein targets and mechanistic pathways through which bioactive plant-derived molecules act simultaneously on both adipose dysfunction and hepatocyte injury.
The review identifies insulin resistance, chronic low-grade inflammation, and mitochondrial impairment as the shared pathophysiological axis linking obesity to metabolic dysfunction-associated steatotic liver disease (MASLD) and its inflammatory-fibrotic progression, MASH. Within this framework, natural products are assessed for their capacity to engage multiple nodes in this axis concurrently — a structural advantage over single-target pharmaceuticals like resmetirom, the thyroid hormone receptor-beta agonist approved for MASH in 2024, which leaves durability and accessibility concerns unresolved. The analysis moves beyond phenotypic observations to pinpoint direct molecular targets, offering mechanistic specificity that earlier natural-product literature often lacked.
This review arrives at a conceptually important moment. The reclassification of nonalcoholic fatty liver disease to MASLD/MASH in 2023 reframed these conditions as systemic metabolic disorders rather than isolated hepatic pathologies — a framing that inherently favors multitarget interventions. Natural compounds, particularly polyphenols, terpenoids, and alkaloids with established safety profiles, are well-positioned within that paradigm. However, several critical caveats apply. Reviews of this type synthesize heterogeneous preclinical data, and most mechanistic insights derive from cell-culture and rodent models with limited human translational validation. Bioavailability remains a persistent bottleneck for most plant-derived compounds, and the absence of large randomized trials means clinical effect sizes are largely unknown. This is a high-quality mechanistic roadmap, but the distance from bench to bedside for these compounds remains considerable.
