TRIM37‐Mediated Ubiquitination and Degradation of KMT2D Activates JAK2‐STAT3 Signaling to Promote Diffuse Large B‐Cell Lymphoma Progression

Diffuse large B-cell lymphoma (DLBCL) is the most common and clinically aggressive subtype of non-Hodgkin lymphoma, yet key molecular drivers remain incompletely defined. Here, we identify the tripartite motif E3 ligase TRIM37 as a disease-relevant oncogenic factor in DLBCL. TRIM37 was markedly upregulated in patient specimens and cell lines, and high expression correlated with poor prognosis. Loss-of-function studies showed that TRIM37 silencing suppressed proliferation and clonogenicity, triggered apoptosis, and restrained tumor growth in vivo. Mechanistically, TRIM37 promoted ubiquitin-proteasome degradation of the enhancer-associated histone methyltransferase KMT2D, reducing H3K4me1 deposition at the SOCS3 regulatory region, repressing SOCS3, and thereby sustaining JAK2-STAT3 phosphorylation. Rescue experiments supported causality: co-silencing KMT2D or enforcing TRIM37 expression reversed these effects, while JAK2 inhibitor treatment reproduced the impact of TRIM37 loss. Collectively, these findings show that TRIM37 drives DLBCL progression by destabilizing KMT2D to disable SOCS3-mediated negative feedback on JAK2-STAT3 and highlight TRIM37 as a potential therapeutic target.