Apigenin inhibits liver cancer via mitochondrial apoptosis and Th1/Th2 balance regulation.

Apigenin (API) is a natural compound with an anti-cancer effect. This study aimed to investigate the mechanism of API against liver cancer. In vitro and in vivo, Huh7 cells and H22-induced liver orthotopic hepatoma model were constructed to assess the anti-tumor effect of API. Cell viability, apoptosis, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), spleen lymphocyte differentiation, relative factors, and tumor pathological damage were determined using cell counting kit-8, flow cytometry, enzyme-linked immunosorbent assay, western blot, immunofluorescence, Hematoxylin-Eosin staining, and TUNEL. API inhibited liver cancer cell viability and promoted apoptosis both in vitro and in vivo. API increased ROS, interleukin (IL)-1β/6/8 and tumor necrosis factor (TNF)-α, expression of cleaved-Caspase-3/9, B-cell lymphoma-2 associated X protein, and phosphorylated nuclear transcription factor-kappa B proteins, while it reduced MMP of Huh7 cells. API increased interferon (IFN)-γ+ CD4+ cells (Th1) and decreased IL-4+ CD4+ cells (Th2) with increasing tumor TNF-α and IFN-γ and decreasing IL-1β and IL-4. The anti-tumor and T-cell regulating effects of API are similar to those of positive control cyclophosphamide. This study displayed that API has the potential to effectively prevent liver cancer by triggering mitochondrial apoptosis, thereby regulating the Th1/Th2 balance. Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-025-00868-7.