TRIM24 promotes T-cell lymphoma development and glucocorticoid resistance via FUS-mediated phase separation of the glucocorticoid receptor.

T-cell lymphoma (TCL) is an aggressive malignancy with poor therapeutic outcomes, where glucocorticoid (GC) resistance remains a major challenge. Here, we identify TRIM24 as a critical regulator of GC receptor (GR) activity and a potential therapeutic target in TCL. TRIM24 deficiency delays TCL progression in murine models, suppresses cell proliferation, and enhances GC sensitivity by restoring GR transcriptional activity, as evidenced by transcriptomic and chromatin profiling. Mechanistically, TRIM24 interacts with Fused In Sarcoma (FUS) and promotes its liquid-liquid phase separation (LLPS) with GR, leading to impaired GR activity and heightened GC resistance. Moreover, TRIM24 is overexpressed in peripheral T-cell lymphoma (PTCL) samples, correlating with suppressed GR signaling and poor therapeutic response. These findings uncover an unrecognized "double-check" mechanism in which TRIM24 regulates nuclear GR function through FUS-facilitated LLPS. Importantly, targeting TRIM24 may provide a novel therapeutic strategy not only for overcoming GC resistance in TCL but also for addressing broader GR-dependent diseases.