CD59 silencing enhances doxorubicin sensitivity in DLBCL cells and is associated with poor prognosis in patients treated with CHOP regimen.

[UNLABELLED] Diffuse large B-cell lymphoma (DLBCL) remains challenging due to high relapse and refractory rates after R-CHOP therapy. The role of complement regulatory protein CD59 in DLBCL progression and drug resistance is poorly understood. This study aimed to investigate the effects of knocking-down complement-regulatory protein, CD59, on disease progression, and chemo-resistance in DLBCL cells, as well as to establish the clinicopathological relevance and prognostic significance of CD59 in DLBCL. Lentiviral-mediated knockdown of CD59 was established in SU-DHL-4 and U2932 DLBCL cell lines. Cell viability, cell cycle distribution, and apoptosis were assessed using CCK-8 and flow cytometry. Immunohistochemistry for CD59 was performed on tumor biopsies from 103 treatment-naive DLBCL patients. Survival analyses were conducted using Kaplan-Meier and Cox regression models. Stable silencing of CD59 significantly reduced cell viability, induced G/G arrest, and promoted apoptosis in both cell lines. The combination with doxorubicin resulted in enhanced growth inhibition and apoptosis compared to monotherapy. In clinical samples, CD59 positivity ( = 43, 41.75%) was correlated with a higher IPI score ( < 0.05), elevated LDH ( < 0.05), and a poorer response to therapy (CHOP,  < 0.05). In CHOP-treated patients, CD59 + predicted shorter PFS (rate, 9.1% vs. 61.4%,  < 0.05) and OS (45.5% vs. 86.9%,  < 0.05), while no significant difference was observed in the R-CHOP subgroup. Multivariate analysis confirmed that CD59 overexpression was an independent predictor of poor PFS and OS (HR = 4.254,  < 0.05). CD59 knockdown suppresses DLBCL cell growth and enhances doxorubicin sensitivity in vitro. Clinically, the prognostic value of CD59 is highly treatment-regimen dependent: high CD59 expression is an independent predictor of poor prognosis specifically in CHOP-treated DLBCL patients, but not in those receiving the standard R-CHOP regimen. These findings highlight CD59 as a potential modulator of chemotherapy response rather than a broadly applicable biomarker.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s10238-026-02134-2.