The inwardly rectifying potassium channel KCNJ12 regulates the stemness of hepatocellular carcinoma cells through the Wnt/β-catenin pathway.

Emerging evidence implicates tumor stemness features-characterized by self-renewal capacity, microenvironment adaptability, and immune evasion mechanisms-as critical determinants of therapeutic resistance and recurrence in hepatocellular carcinoma (HCC). KCNJ12, an inward rectifier potassium channel, has shown electrophysiological functions in cardiomyocytes; however, its oncogenic potential and the role in hepatocarcinogenesis involving cancer stemness regulation remain unexplored. This study systematically characterizes the KCNJ12-mediated molecular pathway driving HCC tumorigenicity. Lentiviral-mediated overexpression and knockdown models with functional assessments revealed KCNJ12's critical role in maintaining cancer cell self-renewal capacity. Mechanistic studies using cycloheximide chase assays, Wnt pathway modulators (LiCl, SKL2001, and salinomycin), and protein interaction analyses demonstrated that KCNJ12 stabilizes β-catenin through the physical interaction with lipoprotein receptor-associated protein 6 (LRP6), disrupting AXIN/APC/GSK-3β complex assembly and subsequent proteasomal degradation. The nuclear β-catenin accumulation drives TCF/LEF-dependent transcriptional activation and thus enhances the self-renewal capacity of HCC cells. Our findings establish KCNJ12 as a novel Wnt/β-catenin regulator and propose dual therapeutic strategies against HCC-mediated chemoresistance: pharmacological suppression of KCNJ12 channel activity and targeted disruption of KCNJ12-LRP6 protein interactions. This mechanistic framework advances our understanding of stemness regulation in HCC and provides feasible targets for developing next-generation anti-HCC therapies.