Vitamin D receptor isoform VDRA suppresses hepatocellular tumorigenesis by restricting YAP nuclear localization

Hepatocellular carcinoma (HCC) frequently arises from uncontrolled proliferation of hepatocyte epithelium, a process potently driven by the transcriptional regulator yes-associated protein (YAP). Although 1,25(OH)₂D₃, the active form of vitamin D, exerts established anti-proliferative effects through its receptor (VDR), the specific roles of its two principal isoforms, VDRA and VDRB1, have remained largely undefined. Clinical analysis of the TCGA-LIHC database identified high VDRB1 and low VDRA expression as robust independent risk factors for poor prognosis, suggesting their divergent impacts on HCC progression. Here, we demonstrated that 1,25(OH)₂D₃ induced coordinate expression of both VDR isoforms in HCC cells, activated divergent transcriptional programs, particularly concerning the regulation of YAP target genes. Crucially, functional overexpression assays revealed that VDRA, but not VDRB1, potently inhibited YAP activation, an effect synergistically augmented by combined treatment with 1,25(OH)₂D₃. This regulatory axis was further substantiated by endogenous VDR silencing, while the VDRA-mediated repression of YAP signaling was substantially abrogated by constitutively active YAP-5SA. Functionally, VDRA impaired the proliferation and colony-forming capacity of HCC cells-an inhibitory action significantly rescued by YAP-5SA overexpression-whereas VDR knockdown promoted cell growth. Mechanistically, VDRA efficiently translocated to the nucleus to restrict YAP nuclear localization, while 1,25(OH)₂D₃-treated VDRB1 formed perinuclear condensates that failed to enter the nucleus. To confirm these mechanisms, we employed patient-derived HCC organoids (validated by H&E, RNA-seq, and WES). Subcutaneous engraftment demonstrated that VDRA overexpression, but not VDRB1, profoundly suppressed tumor growth by attenuating YAP activity. Taken together, our findings establish the VDRA isoform as the primary mediator of 1,25(OH)₂D₃-induced tumor suppression in HCC. By demonstrating that VDRA curtails hepatocarcinogenesis specifically by restricting YAP nuclear localization, this study delineates a novel isoform-specific mechanism within the vitamin D signaling axis, nominating VDRA as a promising biomarker and therapeutic target for YAP-driven liver cancer.