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 anti-ferroptosis genes. In vivo study reveals that CTSS depletion, achieved through either shRNA or the specific inhibitor LY3000328, in combination with a ferroptosis inducer, inhibits HCC tumor growth in orthotopic xenograft mouse models. In conclusion, the above data suggest that CTSS can potentiate ferroptosis in HCC cells and may be a therapeutic target to overcome ferroptosis resistance in HCC patients.