Serine-threonine kinase 38 exerts a cancer-promoting role in hepatocellular carcinoma by stabilizing the Notch intracellular domain

Serine/threonine kinase 38 (STK38) has been increasingly recognized as a tumor-associated kinase across multiple human cancer types. Nevertheless, its potential contribution to the malignant progression of hepatocellular carcinoma (HCC) remains unexplored. The present study was therefore designed to characterize the expression landscape of STK38 in HCC and to delineate its regulatory impact on HCC cell behaviors and the underlying molecular circuitry. STK38 was robustly overexpressed in HCC tumor specimens, and this upregulation showed a clear association with unfavorable clinical outcomes. Silencing STK38 in HCC cell lines substantially attenuated cellular proliferation, migratory capacity, and invasive potential, while concomitantly augmenting the chemosensitivity of the cells. Further mechanistic dissection uncovered a tight functional link between STK38 and the Notch pathway in HCC. STK38 silencing provoked a marked reduction in the protein abundance of NICD1 as well as the canonical Notch downstream effectors HEY1 and HES1. The use of proteasome inhibitors reversed the decline in NICD1 expression induced by STK38 silencing, and overexpression of STK38 significantly reduced the degradation rate of NICD1 protein. Additionally, expressing NICD1 in STK38-silenced cells largely neutralized the tumor-suppressive effects of STK38 silencing. In a subcutaneous xenograft model, STK38 silencing significantly compromised the tumorigenic capacity of HCC cells in vivo, concomitant with suppressed Notch1 pathway activity within the tumor mass. Collectively, these findings position STK38 as a pivotal oncoprotein in HCC, acting at least in part through post-translational stabilization of NICD1 and the consequent activation of the Notch signaling axis. This work not only advances our mechanistic understanding of HCC pathogenesis but also highlights the STK38–NICD1–Notch axis as a candidate therapeutic target for this disease.