NFAT2 promotes sorafenib resistance in hepatocellular carcinoma cells by modulating calcium ion signalling

Treating hepatocellular carcinoma (HCC) remains challenging due to the drug resistance of HCC cells, which limits the clinical efficacy of sorafenib. This study elucidates the role of nuclear factor activated T cells 2 (NFAT2) in sorafenib resistance in HCC cells and reveals the underlying mechanism. Sorafenib-resistant cell lines were constructed, with NFAT2 overexpressed and knocked down via genetic engineering. Fura-2 detected intracellular calcium ion concentration; transmission electron microscopy (TEM) assessed organelle damage; wound healing and transwell assays evaluated cell migration and invasion; clone formation and CCK8 assays measured cell proliferation. Flow cytometry detected apoptosis; Western blot analyzed protein expressions. Tumorigenesis was evaluated using a sorafenib-resistant HCC orthotopic xenograft mouse model. We found that NFAT2 was upregulated in MHCC97H-SR and HepG2-SR cells. Overexpression of NFAT2 inhibited Ca²⁺ influx in MHCC97H-SR, reduced the expression of Ca²⁺ regulation-related proteins (p-PLCγ, p-IP3R, p-CaMKII), ER-related proteins (CPR94, CPR78), and oxidative stress-related proteins (NOX2, NOX4). NFAT2 overexpression inhibited apoptosis and enhanced cell migration, invasion, and proliferation. NFAT2 knockdown reduced tumorigenesis. Our study uncovered a mechanism by which NFAT2 increases HCC cell resistance to sorafenib by altering intracellular calcium ion signals, highlighting NFAT2 as a promising target for HCC drug therapy.