Hepatocellular carcinoma and vitamin D metabolism: novel targets and therapeutic strategies

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide. While age-standardized incidence and mortality have declined in some regions, the overall global burden continues to increase because of population aging and persistent etiologic factors. Curative options are limited to selected patients, and systemic therapies provide modest long-term benefit. Beyond its canonical role in calcium-phosphate homeostasis, vitamin D signals through the nuclear vitamin D receptor (VDR) to modulate immunity, oxidative stress, fibrosis, and cellular metabolism. In HCC, this axis is frequently dysregulated, including downregulation of CYP2R1, reduced CYP27B1 activity, upregulation of CYP24A1, and VDR dysfunction, which together blunt the antitumor actions of vitamin D and are linked to inflammation, aberrant lipogenesis, and immune evasion. Here, we summarize mechanisms by which vitamin D impacts key oncogenic pathways in HCC, including PI3K/AKT/mTOR, IL-6/STAT3, NF-κB, and TGF-β/SMAD, and highlight downstream nodes such as SREBP-1 and TXNIP as potential therapeutic targets. We also discuss emerging strategies to restore vitamin D signaling, such as CYP24A1 inhibition, next-generation vitamin D analogs, and VDR-biased agonists, to facilitate clinical translation and drug development. Vitamin D metabolism and signaling are frequently dysregulated in hepatocellular carcinoma (HCC), including CYP2R1 downregulation, CYP27B1 suppression, CYP24A1 overactivation, and VDR silencing. Vitamin D exerts antitumor effects in HCC through anti-inflammatory, antioxidant, antifibrotic, and metabolic reprogramming pathways. SREBP-1 and TXNIP are identified as novel vitamin D–related molecular targets with potential therapeutic value in HCC. Vitamin D analogs, CYP24A1 inhibitors, and VDR-biased agonists represent promising strategies for overcoming resistance and optimizing HCC treatment.