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Cell Death Discovery

Cell Death Discovery

IF: 6.1
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Combination of HDAC inhibitor and PI3K inhibitor suppresses autophagy and induces apoptosis via cytoplasmic IκBα stabilization in p53-mutant diffuse large B-cell lymphoma

Published:6 October 2025 DOI: 10.1038/s41420-025-02756-7 PMID: 41053160
Jingwei Yao,?Mengqi Li,?Yuelong Jiang,?Nanye Yao,?Yating Liu,?Liemei Lv,?Yuchen Li,?Jiewen Huang,?Jie Zha,?Bing Xu

Abstract

p53-mutant (p53-MUT) diffuse large B-cell lymphoma (p53+ DLBCL) remains a treatment-refractory DLBCL subtype lacking effective therapies. In this study, we systematically validated the synergistic therapeutic potential of HDAC inhibitor chidamide and PI3K inhibitor duvelisib in p53+ DLBCL through cellular models, in vivo experiments, and clinical samples. The combination regimen demonstrated robust induction of apoptosis across multiple p53+ DLBCL cell lines and primary clinical samples. Furthermore, it effectively reduced tumor burden in xenograft mouse models and prolonged overall survival. To elucidate the underlying mechanisms, clinical DLBCL tumor specimens from patients with p53-mutated and p53-wild-type genotypes, as well as p53+ DLBCL cell line samples before and after treatment with chidamide and duvelisib, were collected for RNA-seq analysis. Mechanistically, the combination stabilized IκBα via dual inhibition of PI3Kδ and HDAC2, thereby suppressing NF-κB-p65 phosphorylation and subsequent nuclear translocation, concurrently inhibiting autophagy. These pathway disruptions collectively led to tumor proliferation arrest and potentiation of apoptosis. Specifically, duvelisib inhibited IKK phosphorylation to prevent IκBα degradation, while chidamide enhanced acetylation of histone H1.5 by targeting lysine residues at positions K67 and K93. This acetylation promoted histone H1.5-IκBα interactions, further stabilizing IκBα and attenuating p65 nuclear trafficking. Our findings identify a novel and potent therapeutic strategy for p53+ DLBCL, warranting clinical translation.

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Materials
Procduct Name CAS Molecular Formula Supplier Price
IPI 145 1201438-56-3 C22H17ClN6O 205 suppliers $18.00-$2550.00
IPI 145 1201438-56-3 C22H17ClN6O 205 suppliers $18.00-$2550.00
IPI 145 1201438-56-3 C22H17ClN6O 205 suppliers $18.00-$2550.00
IPI 145 1201438-56-3 C22H17ClN6O 205 suppliers $18.00-$2550.00

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