Omics-based insights into human liver reveal GTPase-driven mechanisms of MASLD progression in obesity

Metabolic dysfunction-associated steatotic liver disease (MASLD) is generally asymptomatic in the early stages but, without appropriate intervention, it can progress to severe liver morbidities. To elucidate the molecular mechanisms of early development of MASLD, we performed transcriptomic analysis on liver biopsies and metabolomic analysis on liver and plasma samples from 109 obese individuals with no liver pathology or early stages of MASLD. The liver metabolome is remodeled by the parenchymal accumulation of neutral lipids, whereas the plasma metabolome displayed little differences. The liver transcriptome revealed that the progression of steatosis and fibrosis is characterized by distinct gene expression signatures. While metabolic remodeling characterizes steatosis, global rewiring of gene expression underpins fibrosis progression. Importantly, GTPases and their regulators were identified as a novel signature for the transition from steatosis to fibrosis. GTPase genes and their regulators were associated with hepatic fibrosis grades and co-expressed with TGF-β signaling. We further verified the involvement of GTPase regulation in fibrogenesis in HSC-like LX-2 cells and a 3D liver spheroid model of primary human hepatocytes and non-parenchymal cells. Our study suggests that modulation of GTPase signaling is a potential therapeutic entry point for the treatment of early liver fibrosis in MASLD.