Shikonin in Hepatocellular Carcinoma: Bridging Metabolic Disruption and Immunomodulation.

Hepatocellular carcinoma (HCC) is characterized by extensive metabolic changes and an immunosuppressive microenvironment, which interact to promote tumor progression, drug resistance and immune escape. Shikonin, a natural naphthoquinone, exhibits broad antitumor activity and may simultaneously affect metabolic and immune pathways. This review synthesizes current evidence on the role of shikonin in HCC through the metabolic-immune axis. Shikonin suppresses glycolysis mediated by pyruvate kinase M2 (PKM2), disrupts the signaling axis involving PKM2, prolyl hydroxylase domain 3 (PHD3), and hypoxia-inducible factor 1-alpha (HIF-1α), impairs mitochondrial function, and promotes reactive oxygen species accumulation, thereby destabilizing metabolic homeostasis and adaptive survival. It also induces apoptosis and immunogenic cell death (ICD)-associated responses in HCC-related models, whereas evidence for necroptosis remains limited and requires further causal validation. In nanodelivery-based HCC models, the release of damage-associated molecular patterns (DAMPs) has been associated with dendritic cell maturation, antigen presentation, cluster of differentiation 8 (CD8⁺) T-cell activation, and improved responses to immune checkpoint blockade. Shikonin has also shown potential in overcoming multidrug resistance and in smart delivery platforms. In conclusion, shikonin emerges as a multi-target agent that acts as a molecular bridge between metabolic stress and immunomodulation, although the evidence for specific mechanistic modules varies in strength.