Work

Targeting cholesterol metabolism to overcome Zanubrutinib resistance in activated B-cell-like diffuse large B-cell lymphoma

Year: 2026

Type: article

Abstract: ABSTRACT Bruton tyrosine kinase (BTK) inhibitor Zanubrutinib shows considerable potential for treating activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL). However, its efficacy is often limited by unresolved resistance mechanisms. In this study, we employed single-cell RNA sequencing (scRNA-seq) to profile Zanubrutinib-resistant ABC-DLBCL cells and identified pronounced upregulation of cholesterol biosynthesis pathways, accompanied by increased expression of HMGCS1, HMGCR, and CYP51A1 in resistant cells. Interestingly, Zanubrutinib treatment failed to suppress the overexpression of these enzymes, leading to a cholesterol-dependent resistance. Further investigation revealed that this resistance mechanism is accompanied by significant remodeling of the tumor microenvironment, featuring substantial cholesterol accumulation that may be facilitated by CD206 + macrophage-mediated cholesterol efflux. Using an integrative approach guided by scRNA-seq data, we combined connectivity mapping with drug repositioning strategies and identified Atorvastatin, an FDA-approved HMGCR inhibitor, as a promising combinatorial agent with Zanubrutinib. Atorvastatin effectively suppressed cholesterol biosynthesis, while Zanubrutinib mitigated the compensatory upregulation of HMGCS1, HMGCR, and CYP51A1 triggered by Atorvastatin monotherapy, resulting in synergistic anti-tumor activity against resistant DLBCL cells. Additional RNA sequencing and functional assays suggested that downregulation of AID, a crucial regulator of B-cell activity and drug resistance due to its ability to induce genomic instability, may underlie the synergistic effect of this combination. Collectively, our findings support a potential role for cholesterol metabolic reprogramming and AID upregulation in reduced Zanubrutinib sensitivity and provide a preclinical rationale for further evaluation of atorvastatin combined with Zanubrutinib in ABC-DLBCL.

Source: Medicine in Novel Technology and Devices

DOI: 10.1016/j.medntd.2026.100468