Inhibition of CDGSH iron‑sulfur domain 2 exhibits tumor-suppressing effects on diffuse large B-cell lymphoma (DLBCL) by inducing ferroptosis through the regulation of the NRF2/SLC7A11/GPX4 pathway

Abstract

CDGSH iron‑sulfur domain 2 (CISD2) is recognized as a ferroptosis-related gene that has potential as a target for cancer treatment. However, it is still uncertain whether targeting CISD2 can modulate ferroptosis in diffuse large B-cell lymphoma (DLBCL) cells and exhibit cancer-suppressing effects. The present study thoroughly investigated the role of CISD2 in DLBCL. CISD2 was found to be overexpressed in DLBCL, and its inhibition resulted in substantial growth inhibition in DLBCL cells. The growth inhibition effect resulting from CISD2 silencing could be reversed by a ferroptosis inhibitor, whereas inhibitors of apoptosis and necrosis did not yield the same reversal. CISD2-silenced DLBCL cells exhibited increased sensitivity to growth inhibition induced by ferroptosis suppressors. The inhibition of CISD2 induced ferroptotic cell death in DLBCL cells, which was supported by the overproduction of lipid peroxides, depletion of glutathione, accumulation of iron, and increased presence of shrunken mitochondria. Further investigation revealed reduced levels of NRF2, GPX4, and SLC7A11 in CISD2-silenced DLBCL cells. The overexpression of NRF2 significantly reduced the occurrence of ferroptotic cell death in DLBCL cells in which CISD2 was silenced. Furthermore, CISD2 inhibition exhibited tumor-suppressing effects in vivo associated with the induction of ferroptotic cell death in xenografts. These findings suggest that CISD2inhibition has tumor-suppressing effects on DLBCL by promoting ferroptotic cell death via the NRF2/SLC7A11/GPX4 pathway. Therefore, CISD2 holds promise as a viable candidate target for treating DLBCL.