CBX4 stabilizes NEUROD1 through SUMO-ubiquitin crosstalk to delay β-cell senescence.

Aging-associated β-cell senescence is a key driver of type 2 diabetes mellitus (T2DM). However, its associated molecular mechanisms remain poorly explored. This study identifies Chromobox 4 (CBX4), a Polycomb group protein with SUMO E3 ligase activity, as an essential regulator of β-cell aging and function. The results show that CBX4 expression progressively downregulates in both aged and diabetic pancreatic islets. Targeted deletion of Cbx4 in β-cell accelerates cellular senescence, impairs glucose tolerance, and compromises mitochondrial function. CBX4 interacts directly with the transcription factor NEUROD1 via its SUMO-interacting motif 1 (SIM1). CBX4 promotes SUMOylation of NEUROD1 at lysine 38 and drives its assembly into nuclear condensates via phase separation. These processes collectively antagonize NEDD4-mediated ubiquitination at the same site, stabilizing NEUROD1. The preserved NEUROD1 enhances Ins2 transcription and suppresses Camk2n1 expression, thus activating CaMKII signaling, promoting calcium influx, and maintaining mitochondrial bioenergetics. Furthermore, the study identifies STAT5A as a transcriptional regulator upstream of Cbx4. These findings reveal a STAT5A-CBX4-NEUROD1 signaling axis associated with β-cell aging in T2DM and suggest CBX4 as a promising therapeutic target to maintain β-cell function in metabolic disorders.