CBX5 loss drives Pl3Kδ inhibitor resistance in mantle cell lymphoma and propolis restores sensitivity by inducing CBX5-mediated ferroptosis

  • Phytomedicine. 2025 Jul 25:143:156911. doi: 10.1016/j.phymed.2025.156911.
Jun Lu  1 ,  Ya-Qin Yang  1 ,  Jia-Yi Tang  1 ,  Si-Yue Lou  2 ,  Chen Wang  1 ,  Hong-Tao Hu  1 ,  Ya-Nan Zheng  1 ,  Hai An  3 ,  Mao-Wei Ni  4 ,  Hua-Jun Zhao  5
Affiliations
  • 1. School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 311402, China.
  • 2. School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 311402, China; Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
  • 3. Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
  • 4. The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China.
  • 5. School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 311402, China; Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China. Electronic address: [email protected].
PMID: 40466505 DOI: 10.1016/j.phymed.2025.156911
Abstract

Background: The generation of drug-resistance limits chemotherapy application such as phosphoinositide 3-kinase δ (PI3Kδ) inhibitors in mantle cell lymphoma (MCL). Propolis has been regarded as a resistance reversal agent for many tumors, but its role in the sensitivity of MCL to PI3Kδ inhibitors remains unclear.

Purpose: The study investigated the synergistic effect, material basis and underlying mechanism of propolis in PI3Kδ inhibitor-resistant MCL cells.

Methods: A PI3Kδ Inhibitor resistance-acquired model was established and proteomics was utilized to identify differentially expressed proteins. The ethanol extract of propolis (EEP) was obtained and its components were detected by using UPLC-Q-TOF-MS/MS analysis. Active ingredients with potential resistance-reversal effect were obtained by reverse pharmacology. The sensitizing effect of caffeic acid phenethyl ester (CAPE) on idelalisib was demonstrated by cell viability assay in vitro and tumor-growth study in vivo. RNA-sequencing was applied to obtain CAPE-regulated genes. The occurrence of Ferroptosis was confirmed by relevant detections such as lipid ROS detection. The regulation of chromobox homolog 5 (CBX5) was achieved by molecular inhibitors, transfection of recombinant plasmid or siRNA.

Results: EEP combined with idelalisib synergistically reduced the viability of resistant MCL cells, with CAPE playing a major role. The combination of CAPE and idelalisib combated the growth of idelalisib-resistant MCL cells in vivo and in vitro by inducing Ferroptosis. The CBX5 level influences the sensitivity to PI3Kδ inhibitors, and CAPE reversed resistance in MCL-R by inducing CBX5-mediated Ferroptosis.

Conclusions: CBX5 loss drives Pl3Kδ inhibitor resistance in MCL and CAPE in propolis restores sensitivity by inducing CBX5-mediated Ferroptosis. This is the first study to demonstrate the reversal of PI3Kδ Inhibitor resistance through CAPE-induced Ferroptosis via CBX5 modulation.

Keywords
CAPE; CBX5; Ferroptosis; PI3Kδ inhibitor resistance; Propolis.
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