Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in adults, which characterized by a high degree of heterogeneity in terms of clinical presentation, molecular phenotype, and genetic features. However, approximately 30 %-40 % of patients are refractory to standard chemotherapy, and their prognosis is poor. The emergence of small-molecule inhibitors, such as Bruton's tyrosine kinase inhibitors (BTKi), has greatly improved the treatment of DLBCL
however, drug resistance associated with small-molecule inhibitors has greatly limited their clinical application. In this study, we elucidated the principal genes influencing BTKi sensitivity in DLBCL and delineated the underlying mechanisms. This study identified cyclin-dependent kinase 1 (CDK1) as the central gene influencing BTKi sensitivity in DLBCL cells. The application of RO-3306 effectively promoted the growth and increased the apoptotic rate of DLBCL cells. Furthermore, RO-3306 increased the susceptibility of DLBCL cells to BTKis in both in vitro and xenograft experimental models. RNA-seq analyses suggested the potential modulation of the JAK2/STAT3 signaling cascade by RO-3306, a finding further confirmed by the diminished phosphorylation documented by western blotting. This study provides pivotal insights into the mechanisms governing BTKi sensitivity in DLBCL and potentially reveals new avenues for targeted therapeutic strategies.