Liver Stiffness Rises Early in MASLD and Drives Inflammation, Lipid Dysmetabolism, and Fibrosis via Piezo1–YAP Mechanotransduction

ABSTRACT Metabolic dysfunction–associated steatotic liver disease (MASLD) is shaped by metabolic injury and tissue mechanics. This study investigated whether liver stiffening occurs early in MASLD and how extracellular matrix (ECM) mechanics interact with lipid droplet (LD) overload to promote inflammation, fibrogenesis, and lipid dysmetabolism. Clinical data, mouse models, and in vitro experiments are integrated. Liver stiffness shifted modestly with steatosis but increased substantially in the presence of inflammation. In a diet‐induced mouse model, liver stiffness increased before overt fibrosis. In cultured hepatocytes, stiff matrices combined with free fatty acid (FFA) induced steatosis synergistically amplified pro‐inflammatory and pro‐fibrotic signals, accompanied by cytoskeletal remodeling and nuclear deformation. YAP acted as a central mechanosensitive amplifier: stiffness drove YAP nuclear localization, and YAP knockdown blunted cytokine induction and fibrogenic gene expression under stiff + FFA conditions. Stiffness and LD overload jointly promoted lipogenesis and impaired lipophagy via YAP. Piezo1 is upregulated by stiff + FFA; its inhibition reduced Ca 2 ⁺ influx and prevented YAP activation. Collectively, early liver stiffening, together with LD‐derived intracellular stress, engages a Piezo1–YAP axis that amplifies inflammation, fibrogenesis, and disordered lipid metabolism, consistent with a proposed feed‐forward loop mechanism accelerating MASLD progression.