YAP-mediated mechanotransduction promotes hepatocellular carcinoma progression by targeting ATP1A1/CXCL1 axis

Extracellular matrix (ECM) stiffness is a critical biomechanical factor that plays a key role in tumor progression, influencing tumor behavior and driving its malignancy. Transcriptional co-activator yes-associated transcriptional regulator (YAP) is a well-established mechanosensitive regulator; however, the molecular mechanisms by which matrix stiffness-mediated YAP activation promotes tumor progression through transcriptional regulation remain incompletely defined. Here, using cross-omics analysis, in vitro, and in vivo experiments, we identified ATPase Na⁺/K⁺ transporting subunit alpha 1 (ATP1A1) as a novel target of YAP/TEA domain transcription factor 4 (TEAD4) mechano-responsive transcription factor complex, whose increased expression in stiff matrix promotes tumor cell proliferation. Mechanistically, we revealed that stiff matrix promotes YAP/TEAD4 binding to the ATP1A1 promoter, thereby upregulating its expression. Increased ATP1A1 in turn promotes intracellular calcium signaling and activates the nuclear factor-kappa B (NF-κB) pathway, thereby promoting C-X-C motif chemokine ligand 1 (CXCL1) expression and secretion, and subsequently enhances tumorigenic potential. These findings demonstrate that increased matrix stiffness activates YAP/TEAD4-dependent transcriptional program and promotes ATP1A1 expression, thereby converting mechanical cues into chemical signaling output and finally promoting malignant phenotypes in the tumor. Furthermore, these findings suggest that CXCL1 may contribute to stiffness-associated tumor progression and warrant further investigation as a potential therapeutic target.