TROP2 confers resistance to oxidative stress-induced cancer cell death through YAP/HMOX1 signaling

BACKGROUND: Trophoblast cell surface antigen 2 (TROP2) is overexpressed in non-small cell lung cancer (NSCLC) and associated with poor prognosis, yet its role in ferroptosis—an iron-dependent form of regulated cell death—remains largely unknown. This study investigated the function and underlying mechanism of TROP2 in ferroptosis regulation in lung cancer. METHODS: TROP2 expression was examined in NSCLC tissues and cell lines. Functional assays, including RNA sequencing, qRT-PCR, Western blot, flow cytometry, and transmission electron microscopy, were performed in lung cancer cells with TROP2 knockdown or overexpression. The involvement of the YAP1/HMOX1 axis was evaluated using luciferase reporter assays, immunofluorescence, and nuclear-cytoplasmic fractionation. An in vivo xenograft model was established to assess the effect of TROP2 inhibition combined with the ferroptosis inducer RSL3. RESULTS: TROP2 was significantly upregulated in NSCLC tissues and correlated with worse patient survival. Knockdown of TROP2 sensitized cells to RSL3-induced ferroptosis, as evidenced by increased lipid peroxidation, reactive oxygen species, and malondialdehyde levels, along with reduced glutathione. Mechanistically, TROP2 inhibited nuclear translocation of YAP1, which consequently suppressed transcriptional activation of the key ferroptosis-promoting gene HMOX1. Rescue experiments confirmed that HMOX1 mediates the pro-ferroptotic effect of TROP2 knockdown. In vivo, TROP2 depletion synergized with RSL3 to suppress tumor growth and elevate ferroptosis markers. CONCLUSION: TROP2 confers ferroptosis resistance in NSCLC by inhibiting YAP1 nuclear translocation and subsequent HMOX1 transcription. Targeting TROP2 sensitizes lung cancer cells to ferroptosis inducers, revealing a novel TROP2/YAP1/HMOX1 regulatory axis with therapeutic potential for NSCLC treatment.