CTSB

Overview

Cathepsin B (CTSB) is a lysosomal cysteine protease belonging to the papain superfamily of peptidases. Encoded by the CTSB gene, the protein is ubiquitously expressed across human tissues and is primarily localized within the endosomal–lysosomal compartment, where it participates in the degradation of intracellular proteins, extracellular matrix remodeling, and the processing of newly synthesized lysosomal enzymes. Like other cathepsins, CTSB undergoes proteolytic maturation after synthesis, transitioning from an inactive proform to a catalytically active enzyme in the acidic environment of the lysosome. It functions both as an endopeptidase and as a carboxydipeptidase, giving it a broad substrate range relative to related family members such as cathepsin D.

Beyond its homeostatic roles, CTSB has emerged as a clinically significant factor in oncology, neurodegeneration, and infectious disease. Elevated CTSB expression and secretion have been documented in multiple solid tumors—including pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer—where the enzyme contributes to tumor invasion, immune evasion, and therapy resistance. In the central nervous system, aberrant CTSB activity has been linked to lysosomal dysfunction in Parkinson's disease models, while in helminthic infection, parasite-derived cathepsin B homologs serve as immunodominant antigens. These diverse pathological associations have positioned CTSB as a tractable target for both small-molecule inhibition and enzyme-responsive drug delivery systems.

Focus of Latest Publications

Recent publications have examined CTSB as a functional target in cancer therapy, immunotherapy, neuroprotection, and biomaterials. In hepatocellular carcinoma, CTSB was implicated in a strategy to overcome sorafenib resistance driven by lysosomal sequestration and autophagy, where clomipramine was proposed to potentiate sorafenib efficacy by modulating the cathepsin B/Bcl-2/Beclin-1 axis. In triple-negative breast cancer, cepharanthine was shown to bind directly to lysosomal cathepsin B and cathepsin D, impair their maturation, suppress lysosomal degradation, and trigger apoptosis through TFEB activation, with downstream upregulation of NOXA and downregulation of Bcl-2.

Several studies focused on CTSB as a tumor microenvironment-responsive trigger for engineered therapeutics and imaging. A bioorthogonal in situ PROTAC synthesis platform used overexpressed CTSB, together with glutathione, as an “AND” gate to generate an active GPX4-degrading PROTAC inside tumors, thereby inducing ferroptosis and amplifying cuproptosis and photodynamic therapy-associated reactive oxygen species to promote immunogenic cell death and synergy with anti-PD-L1 therapy. In another imaging study, a photoactivatable cascade DNAzyme nanomachine was designed to monitor cathepsin B activity alongside granzyme B during STING-activated immunotherapy, revealing distinct enzymatic patterns in immune-suppressed versus STING-activated tumors.

Outside oncology, CTSB was also studied in neurological injury and immune cell function. In spinal cord injury, Ctsb emerged as a pivotal gene associated with neuronal viability, and the Ctsb/Ctsl inhibitor K777 improved neuronal survival, reduced oxidative stress, inhibited neuronal apoptosis and proinflammatory cytokine release, promoted axonal growth, and enhanced motor recovery through activation of the PI3K/Akt signaling pathway. In CAR T-cell therapy, cathepsin B inhibition was found to prevent trogocytosis-driven CAR T-cell fratricide and exhaustion, improving long-term CAR T-cell persistence and antitumor activity.

Additional publications highlighted CTSB in antigen design, supramolecular materials, and disease association studies. A nano-cathepsin B proteinase antigen from Trichinella spiralis was evaluated as an immunoprotective vaccine candidate in murine trichinellosis. A supramolecular fiber system incorporated a Cathepsin B-cleavable peptide to enable cooperative light- and enzyme-responsive assembly behavior for potential drug delivery applications. An integrative multi-omics study also implicated a CTSB/ITIH-ECM axis in autism spectrum disorder, although the abstract provided only the study rationale and not detailed results.

Key Publications

NEWJun Clomipramine potentiates sorafenib efficacy in experimental hepatocellular carcinoma by targeting lysosomal sequestration and modulating the cathepsin B/Bcl-2/Beclin-1 axis. (Molecular biology reports, 2026, PMID 42377685): "...modulating the cathepsin B/Bcl-2/Beclin-1 axis."
May The immuno-protective efficacy of Trichinella spiralis nano-cathepsin B proteinase antigen in murine trichinellosis. (Journal of helminthology, 2026, PMID 42169530): "Trichinella spiralis cathepsin B proteins (TsCB) are highly antigenic molecules secreted by the parasite and represent promising candidates for vaccine development."
May Logic-Gated Bioorthogonal In Situ Synthesis of Proteolysis-Targeting Chimeras for Precise Protein Degradation and Synergistic Immunotherapy. (ACS nano, 2026, PMID 42114042): "Only the concurrent action of both inputs enables the bioorthogonal ligation of the fragments in situ to form the active GPX4-degrading PROTAC."
May Cepharanthine inhibits lysosomes and induces apoptosis in triple‑negative breast cancer cells. (Molecular medicine reports, 2026, PMID 42099230): "the present study demonstrated that CEP bound directly to the lysosomal enzymes cathepsin B and cathepsin D, thereby impairing their maturation and suppressing lysosomal degradation."
Apr K777 promotes functional recovery after spinal cord injury via the PI3K/AKT signaling pathway. (Biochemical and biophysical research communications, 2026, PMID 42061005): "High-dimensional weighted gene co-expression network analysis revealed that Ctsb and Ctsl were two pivotal genes that were associated with neuronal viability."
Jun Integrative multi-omics implicates a CTSB/ITIH-ECM axis in autism spectrum disorder. (Neurobiology of disease, 2026, PMID 42019823): "Integrative multi-omics implicates a CTSB/ITIH-ECM axis in autism spectrum disorder."
Apr Preventing trogocytosis by cathepsin B inhibition augments CAR T-cell function. (Signal transduction and targeted therapy, 2026, PMID 42020353): "we found that the cysteine protease cathepsin B is essential for CMT and that inhibition of cathepsin B is sufficient to prevent CAR T-cell fratricide and exhaustion."
May Light and Enzymatic Cooperative Response in Supramolecular Fibers: A Synergistic Strategy for Potential Drug Delivery Applications. (Biomacromolecules, 2026, PMID 41995357): "The synergistic application of two orthogonal stimuli enabled modulation of the assembly of BTA-AZB-GFLG fibers through the cooperative response to stimuli."
Apr Photoactivatable Cascade DNAzyme Nanomachines for Amplified Imaging of Tumor Response to STING-Activated Immunotherapy. (Analytical chemistry, 2026, PMID 41980121): "Herein, we report a near-infrared (NIR) photoactivatable cascade DNAzyme nanomachine (PCDzNM) designed for the concurrent, amplified imaging of granzyme B (Gzm B) and cathepsin B (Cat B) activity during STING-activated immunotherapy."