Wogonin derivative V8 enhances bortezomib efficacy in gastric carcinoma by disrupting lysosome-mediated drug resistance

Figure 8 Schematic diagram illustrating the mechanism by which V8 synergizes with bortezomib to induce cell death in gastric cancer cells. Bortezomib (BTZ) alone is sequestered in lysosomes, resulting in insufficient proteasome inhibition and mild apoptosis. V8 alone induces lysosomal damage and cell death via lysosomal membrane permeabilization and CTSB release. V8 disrupts lysosomes to release sequestered BTZ, enabling potent proteasome inhibition that triggers proteotoxic stress (ubiquitinated protein accumulation, endoplasmic reticulum stress, and mitochondrial stress), ultimately culminating in caspase-dependent apoptosis. BTZ: Bortezomib; TFEB: Transcription factor EB; CLEAR: Coordinated lysosomal expression and regulation; Bip: Immunoglobulin heavy chain binding protein; p-eIF2α: Phosphorylated eukaryotic translation initiation factor 2 alpha; Z-VAD-FMK: Benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone.