Figure 8. Proposed scheme of DCA-induced apoptosis and the role of NHE inhibitors in apoptosis-resistance.

(1) Bile acids damage lysosomes and release the acidic contents into the cytoplasm. (2) Cytoplasmic acidification leads to NHE activation. (3) Na⁺ enters cells in exchange for H⁺. As a result K⁺ exits cells to balance osmolarity and cytoplasmic calcium rises because Na⁺-Ca²⁺ exchange is impaired. (4) Ion imbalance leads to caspase activation and apoptosis. NO or other endogenous inhibitors inhibit NHE and tend to prevent apoptosis induction.