Liquid-liquid phase separation of ZHX2 protects DLBCL cells against ferroptosis through induction of SLC3A2 [ChIP-seq]
Diffuse large B-cell lymphoma (DLBCL), the most common B-cell non-Hodgkin lymphoma (B-NHL), is characterized by strong aggression, high heterogeneity and poor prognosis. Consequently, there is an urgent need to identify crucial therapeutic targets. Here, we found that the transcription factor Zinc-finger and homeoboxes 2 (ZHX2) is highly expressed in DLBCL. Subsequently, ZHX2 was proven to be critical for promoting DLBCL cells proliferation by inhibiting ferroptosis. Mechanistically, ZHX2 binds to the promoter region of the solute carrier family 3-member 2 (SLC3A2) gene through liquid-liquid phase separation (LLPS) and activates its function to negatively regulate ferroptosis. Furthermore, we constructed lipid nanoparticles Zhx2-siRNA@LNP targeting DLBCL, which effectively inhibited the growth of the tumor in vivo. In summary, our study indicated that LLPS of ZHX2 protects DLBCL against ferroptosis through induction of SLC3A2, and disturbing it with Zhx2-siRNA@LNP could significantly repress DLBCL, providing a promising therapeutic strategy for DLBCL. Overall design: ChIP-seq was used to identify the downstream differential molecules that might be regulated between DB-ZHX2 and DB-ZHX2-Mut4