PIEZO1 channel mechanosensing in hepatobiliary physiology and disease

The hepatobiliary system is constantly exposed to dynamic mechanical forces, including fluid shear stress, bile canaliculi pressure, and extracellular matrix stiffness. Although traditionally studied for its metabolic and detoxifying functions, it is now increasingly recognized as a mechanosensitive organ. This review focuses on PIEZO1 mechanically gated ion channels that transduce physical cues into calcium-dependent signaling events. PIEZO2, the only other PIEZO isoform, is not known to be relevant in the hepatobiliary system. We examine the current knowledge on PIEZO1 in liver physiology, highlighting its roles in liver sinusoidal endothelial cells, hepatocytes, and macrophages. In health, PIEZO1 regulates key processes such as bile acid synthesis (through nitric oxide-mediated suppression of <i>CYP7A1</i>), bile flow, antioxidant defense, and iron homeostasis. In disease, PIEZO1 activity is linked to pathological processes such as inflammation, fibrosis, and angiogenesis in the context of cirrhosis and hepatocellular carcinoma. We discuss the idea that the liver alternates between two functional states depending on portal vein flow: a high-flow state favoring detoxification and metabolism, and a low-flow state that prioritizes bile acid production. Understanding how PIEZO1 contributes to these transitions offers new insights into liver's ability to adapt its function and metabolism. Further research on hepatobiliary PIEZO1 will advance the understanding of how physical exercise promotes health and opens new opportunities for enhancing liver regeneration after surgical resection and liver function in chronic diseases such as fibrosis and cirrhosis.