Authors
Juan Ma, Ning Xie, Ziwei Wang, Xiru Liang, Yulong Han, Qiang Zhao, Ming Wang, Hongwei Lu, Wanyi Kou, William Alazawi, Jinhai Wang, Lu Li, Ning Liu, Na Liu, Haitao Shi, Feng Xu
Published in
Advanced science (Weinheim, Baden-Wurttemberg, Germany). Volume 13. Issue 19. Pages e19109. Epub Jan 04, 2026.
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 Ca2⁺ 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.
PMID:
41486513
Bibliographic data and abstract were imported from PubMed on 09 Sep 2026.
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