It is widely accepted that lysosomes are essential for cell homeostasis, and autophagy plays an important role in tumor development. Here, we found FV-429, a synthetic flavonoid compound, inhibited autophagy flux, promoted autophagosomes accumulation, and inhibited lysosomal degradation in T-cell malignancies. These effects were likely to be achieved by lysosomal dysregulation. The destructive effects of FV-429 on lysosomes resulted in blockage of lysosome-associated membrane fusion, lysosomal membrane permeabilization (LMP), and cathepsin-mediated caspase-independent cell death (CICD). Moreover, we initially investigated the effects of autophagy inhibition by FV-429 on the therapeutic efficacy of chemotherapy and found that FV-429 sensitized cancer cells to chemotherapy agents. Our findings suggest that FV-429 could be a potential novel autophagy inhibitor with notable antitumor efficacy as a single agent.

溶酶体对于细胞稳态至关重要，自噬在肿瘤发展中起着重要作用，这一点已被广泛接受。在这里，我们发现 FV-429，一种合成的黄酮类化合物，在 T 细胞恶性肿瘤中抑制自噬通量，促进自噬体积累，并抑制溶酶体降解。这些效果很可能是通过溶酶体失调来实现的。FV-429 对溶酶体的破坏作用导致溶酶体相关膜融合、溶酶体膜透化 (LMP) 和组织蛋白酶介导的半胱天冬酶非依赖性细胞死亡 (CICD) 的阻断。此外，我们最初研究了 FV-429 抑制自噬对化疗疗效的影响，发现 FV-429 使癌细胞对化疗药物敏感。