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Thalidezine triggers Cathepsin B-mediated cell death in T-cell lymphoma by disrupting lysosomal function

Yingjie Qing1, Su Xu2, Dawei Yang3

  • 1State Key Laboratory of Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China.

Chemico-Biological Interactions
|January 22, 2026
PubMed

Insights

Thalidezine, a novel lysosomotropic agent, effectively targets T-cell lymphoma (TCL) by inducing lysosomal membrane permeabilization. This releases Cathepsin B, initiating apoptosis and offering a promising therapeutic strategy for TCL.

Area of Science:

  • Oncology
  • Cell Biology
  • Pharmacology

Background:

  • T-cell lymphoma (TCL) is an aggressive cancer with poor prognosis and resistance to therapy.
  • Targeting cellular lysosomes for cancer cell death is a developing strategy.
  • The therapeutic potential of lysosomotropic agents in TCL requires further investigation.

Purpose of the Study:

  • To evaluate Thalidezine (Tha) as a novel lysosomotropic agent (LA) against T-cell lymphoma (TCL).
  • To elucidate the mechanism of cell death induced by Thalidezine in TCL.
  • To assess the in vivo efficacy of Thalidezine in a mouse model of TCL.

Main Methods:

  • Treatment of TCL cells with Thalidezine.
  • Measurement of lysosomal pH and lysosomal membrane permeabilization (LMP).
  • Assessment of Cathepsin B (CTSB) release and its role in apoptosis via caspase-3 activation.
  • In vivo efficacy studies in NOD/SCID mice bearing TCL xenografts.

Main Results:

  • Thalidezine selectively targeted TCL cells, reducing lysosomal pH and inducing LMP.
  • LMP triggered the release of CTSB into the cytosol, activating caspase-3 and initiating apoptosis.
  • CTSB knockdown significantly protected TCL cells from Thalidezine-induced death.
  • Thalidezine demonstrated significant anti-tumor activity in vivo.

Conclusions:

  • Thalidezine is a potent drug candidate for T-cell lymphoma treatment.
  • The mechanism involves lysosome weaponization, releasing CTSB to trigger apoptosis.
  • This highlights a therapeutically relevant vulnerability in TCL.
Keywords:
CTSBLMPLysosomeLysosomotropic agentTCLThalidezine

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