Fig. 15. The pathway by which TiO₂ NPs induce mitochondria-associated apoptosis in HepG2 cells. The morphology of TiO₂ NPs determines how they enter cells. For example, the monomer may enter cells via free diffusion and αENaC channels, whereas the polymer enters cells via pinocytosis. After that, TiO₂ can accumulate in mitochondria, which depolarizes the mitochondrial membrane and opens VDAC1 channels. Moreover, TiO₂ NPs can reduce the expression level of ACSS1, block the tricarboxylic acid cycle and give rise to an unbalanced ADP/ATP ratio, which results in the extensive accumulation of pro-apoptotic substances (such as Cyt c) in the mitochondria. Afterwards, pro-apoptotic substances can enter the cytoplasm via mitochondrial VDAC1 channels, activate caspase-3/7, cause DNA degradation and promote apoptosis.