Álvarez Corrales, EmigdioMoreno Palomares, RocíoGómez Escolar, CarmenMartínez, MarioMoral Pérez, UdaneLaguna, MaríaFuertes, TeresaEstrada, Belén S.Mur, SoniaBonis, Adriana deEt.al.2026-04-102026-04-102026Álvarez-Corrales, E., Moreno-Palomares, R., Gómez-Escolar, C., Martínez, M., Moral-Pérez, U., Laguna-Herrero, M., Fuertes, T., Estrada, B. S., Mur, S., De Bonis, A., Leiva, M., Martínez-Martín, N., Somoza, Á., Ramiro, A. R., & De Yébenes, V. G. (2026). Targeting of ibrutinib resistance–driving pathways by miR-28 in ABC-DLBCL. Leukemia. https://doi.org/10.1038/s41375-026-02948-91476-55510887-6924https://hdl.handle.net/11268/17019Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive B-cell lymphoma. Although many patients respond well to R-CHOP immunochemotherapy, those with the activated B-cell (ABC) subtype are often refractory or relapse. Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib have improved outcomes, but acquired resistance limits their long-term efficacy. Here, we modeled the development of ibrutinib resistance in ABC-DLBCL and investigated whether the BCR-signaling regulator microRNA-28 (miR-28) can block this process. Using flow cytometry–based competition assays, multicolor clonal barcoding, transcriptomic profiling, and xenograft models, we found that miR-28 expression impairs the emergence of ibrutinib-resistant ABC-DLBCL cells. Mechanistically, miR-28 interferes with the clonal selection process triggered by ibrutinib treatment and rewires transcriptional programs by downregulating mitochondrial and mTOR signaling pathways critical for resistance development. Furthermore, the miR-28–repressed gene signature associated with ibrutinib resistance correlates with improved survival in ibrutinib-treated patients from the PHOENIX trial cohort with the MCD genetic subtype, which is associated with ABC-DLBCL. Finally, the targeted therapeutic delivery of miR-28 via aptamer-guided nanoparticles suppresses ibrutinib-resistant tumor growth in vivo. These findings identify miR-28 as an effective inhibitor of ibrutinib resistance, underscoring its translational potential as an adjunct strategy in ABC-DLBCL therapy.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/BiomedicinaLinfoma de Células B Grandes DifusoMicroARNsDesarrollo de Medicamentosjournal article10.1038/s41375-026-02948-9open accessCáncerTratamiento médicoBiología celularGoal 3: Ensure healthy lives and promote well-being for all at all ages