T-cell lymphoma (TCL) includes various aggressive non-Hodgkin lymphomas that develop from T cells [1,2]. Two representative forms are Adult T-cell leukemia/lymphoma (ATLL), linked to HTLV-1 infection, and acute T-lymphoblastic leukemia (T-ALL), which originates from immature T-cell precursors [[2], [3], [4]]. Despite their differences in clinical features and progression, both neoplastic processes share molecular features, including dysregulated T-cell receptor signaling, aberrant activation of survival pathways, and robust antiapoptotic mechanisms [[5], [6], [7]]. The standard clinical treatment regimen, including combination chemotherapy, targeted agents and hematopoietic stem cell transplantation do not provide satisfactory clinical outcomes, and relapse is frequent, thus these limitations have driven increasing interest in identifying novel vulnerabilities of TCL [2,8].

Lysosomes are the principal acidic organelles in eukaryotic cells. In 1974, Duve first discovered that some drugs tend to accumulate in late endosomes or lysosomes [9,10]. Drugs with this characteristic are termed as lysosomotropic agents (LA) [[11], [12], [13]]. Due to the role of lysosomes in cellular metabolism, nutrient recycling and cellular pathways that are necessary for survival and growth, they are critical in sustaining the increased proliferative rate of TCL, thus cancer cells rely heavily on lysosomes [[14], [15], [16]]. Lysosomal content, size and structure are frequently altered in TCL (16). These modifications make cancer cells vulnerable to Lysosomal Membrane Permeabilization (LMP). LA that induce LMP have been identified as a novel class of anticancer drugs [17,18].

Despite their diverse chemical structures, most of them contain an amino group and are weak bases. These drugs are relatively nonpolar and can pass through these membranes to the acidic organelles in these cells in the cytoplasm. However, these organelle-internalized drugs become protonated and positively charged due to the acidic pH inside the organelles, which dramatically increases their polarity [19]. There they cannot diffuse again through the organelle membrane and are trapped in the organelle. LA can be classified into two categories: One is hydrophilic lysosomotropic compounds, such as ammonia (NH3). The other is lipophilic or amphiphilic lysosomotropic compounds, which possess one or more hydrophobic ring structures and a hydrophilic tail (mostly an amino group) [20]. Many tricyclic antidepressants, antihistamines, and chloroquine (CQ) belong to the second category [21]. The hydrophobic structures of these drugs facilitate their accumulation in lysosomes, where they interfere with membrane-associated proteins, alkalinize this organelle, and impair lysosomal function [19,22].

In this study, we introduce Thalidezine (Tha), a novel and potent LA derived from the active components of Radix Et Rhizoma Thalictri, a traditional Chinese medicine. As a LA, Tha was enriched in TCL lysosomes, causing LMP and leading to the release of Cathepsin B (CTSB). This release triggers the CTSB-caspase pathway, initiating apoptosis and thereby effectively killing TCL cells. Our findings not only highlight Tha as a potential therapeutic agent but also provide new insight into lysosomal dysfunction as a target for TCL therapy. This work underscores the therapeutic potential of lysosome-targeted strategies in treating TCL.