Celastrol induces liver cancer cell death via TFEB-mediated lysosome activation and ROS-dependent ferroptosis.

The development of effective and low-toxicity therapies for liver cancer and other malignancies remain an unmet clinical challenge, primarily due to dysregulated cancer cell proliferation and therapeutic resistance. In this study, we demonstrate that the natural compound celastrol effectively overcomes this by inducing a coordinated cell death program through transcription factor EB (TFEB)-mediated lysosomal activation. Mechanistically, celastrol facilitates TFEB nuclear translocation, enhancing lysosomal biogenesis and triggering ferritinophagy. The subsequent release of free iron, in conjunction with celastrol-induced accumulation of reactive oxygen species (ROS), leads to lethal lipid peroxidation and ferroptosis. Furthermore, this peroxidative stress activates the pro-apoptotic protein Bid, cascading the ferroptotic signal into mitochondrial apoptosis. Notably, TFEB overexpression amplifies the anticancer efficacy of celastrol, whereas TFEB knockdown or lysosomal inhibition abrogates celastrol-induced cytotoxicity, confirming the critical role of the lysosomal pathway. Collectively, our study elucidates a novel TFEB‑lysosome‑ferroptosis‑apoptosis axis as the mechanistic foundation for celastrol's anticancer properties, underscoring its therapeutic promise against liver cancer and potentially other malignancies with similar vulnerabilities.