Nanosize Non‐Viral Gene Therapy Reverses Senescence Reprograming Driven by PBRM1 Deficiency to Suppress iCCA Progression

Abstract Polybromo‐1 (PBRM1) serves as a crucial regulator of gene transcription in various tumors, including intrahepatic cholangiocarcinoma (iCCA). However, the exact role of PBRM1 in iCCA and the mechanism by which it regulates downstream target genes remain unclear. This research has revealed that PBRM1 is significantly downregulated in iCCA tissues, and this reduced expression is linked to aggressive clinicopathological features and a poor prognosis. Furthermore, it is demonstrated that PBRM1 can impede iCCA progression, and a gene therapy nanomedicine is developed to treat iCCA in vivo by modulating PBRM1 expression. The heightened expression of PBRM1 induces by the nanomedicine substantially inhibited tumor growth in iCCA. Conversely, the decrease in PBRM1 results in the abnormal activation of the ERK1/2 signaling pathway, a reduction in p16, p53/p21, and cellular senescence, thereby promoting iCCA advancement. Treatment with U0126, an ERK1/2 inhibitor, effectively halted iCCA progression by regulating the PBRM1‐ERK1/2‐cellular senescence pathway. These findings underscore the significant role of PBRM1 in controlling iCCA progression and predicting prognosis. Targeting the PBRM1‐ERK1/2‐cellular senescence pathway with U0126 shows promise for clinical applications in treating iCCA.