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.