["Clinical and Experimental Pharmacology and Physiology, Volume 53, Issue 5, May 2026. ", "\nABSTRACT\nHypertension promotes cardiac fibrosis and ultimately leads to heart failure. Piezo1, a new mechanically sensitive cation channel, can transduce mechanical stress into biochemical signals that are necessary for cellular physiological and pathological functions. Although some studies have shown that Piezo1 is involved in the occurrence of cardiovascular disease, whether Piezo1 participates in hypertension‐induced cardiac fibrosis, and the detailed molecular mechanisms are still unclear. Experiments were performed on cardiac tissue from spontaneously hypertensive rats (SHRs) and angiotensin II (Ang II)‐treated mice. Rat cardiac fibroblasts (RCFs) were exposed to high hydrostatic pressure (HHP, 120 or 180 mmHg) using a self‐developed device. We found that Piezo1 expression and β‐catenin activation were markedly elevated in the cardiac tissue of hypertensive animals and in HHP‐treated RCFs, accompanied by elevated expression of fibrosis factors, including TGF‐β1, collagen I and collagen III. Furthermore, the inhibition or knockdown of Piezo1 (GsMTx4 and siRNA) and β‐catenin (XAV939) alleviated TGF‐β1, α‐SMA and collagen expression in HHP‐induced RCFs. Importantly, inhibition of Piezo1 decreased the concentration of intracellular Ca2+ and the nuclear translocation of β‐catenin. Knockdown of Piezo1 in Ang II‐treated mice ameliorated hypertension‐induced myocardial fibrosis. Overall, Piezo1 channel activation caused by HHP could result in an increased concentration of intracellular Ca2+ and subsequently mediate the nuclear translocation of β‐catenin, leading to the synthesis and secretion of collagen by RCFs. This indicates that targeting Piezo1 could be a potential novel approach for treating cardiac fibrosis induced by hypertension.\n"]