Cathepsin S regulates ferroptosis sensitivity in hepatocellular carcinoma through the KEAP1-NRF2 signaling pathway.

ABSTRACT: Ferroptosis is a newly discovered iron-dependent programmed cell death characterized by excess lipid peroxidation. It is emerging as a promising target for tumor therapies. In the present study, we first identify Cathepsin S (CTSS) as a novel ferroptosis regulator. CTSS is upregulated in ferroptosis-resistant hepatocellular carcinoma (HCC) cells, and suppression of CTSS sensitizes HCC cells to ferroptosis. Mechanistically, ferroptosis stress induces CTSS maturation and promotes the autophagy-lysosomal degradation of Kelch-like ECH-associated protein 1 (KEAP1). This process blocks KEAP1-dependent, ubiquitination-mediated degradation of nuclear factor E2-related factor 2 (NRF). Consequently, the accumulated NRF2 translocates from the cytoplasm to the nucleus and drives the transcription of a

SUBMITTER: Xu RC 

PROVIDER: S-EPMC12357265 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature