Cathepsin B (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.

Recent Publications Summary

Recent studies have examined Cathepsin B (CTSB) as a functional target in cancer, neuroinflammation, immunotherapy, and biomaterials, often in the context of lysosomal activity or protease-responsive delivery systems. In hepatocellular carcinoma, clomipramine was reported to potentiate sorafenib efficacy by targeting lysosomal sequestration and modulating the cathepsin B/Bcl-2/Beclin-1 axis, linking CTSB to drug retention and autophagy-related resistance mechanisms 42377685Jun. In triple-negative breast cancer, cepharanthine was found to bind directly to cathepsin B and cathepsin D, impair their maturation, suppress lysosomal degradation, and trigger apoptosis with associated changes in NOXA, Bcl-2, mitochondrial membrane potential, and TFEB nuclear accumulation 42099230May.

CTSB has also been investigated as a therapeutic target in immune and neurological settings. In CAR T-cell therapy, cathepsin B inhibition was shown to prevent trogocytosis, thereby reducing CAR T-cell fratricide and exhaustion and improving long-term CAR T-cell persistence and antitumor activity in vitro and in vivo 42020353Apr. In spinal cord injury, Ctsb was identified alongside Ctsl as a pivotal gene associated with neuronal viability, and the Ctsb/Ctsl inhibitor K777 improved neuronal viability, reduced oxidative stress, inhibited neuronal apoptosis and pro-inflammatory cytokine release, and promoted axonal growth, with downstream involvement of the PI3K/Akt signaling pathway 42061005Apr.

Several recent studies used CTSB as a stimulus-responsive element in engineered platforms. A supramolecular fiber system incorporated a GFLG sequence responsive to Cathepsin B activity and light, enabling cooperative control of fiber assembly for potential drug delivery applications 41995357Apr. A near-infrared photoactivatable cascade DNAzyme nanomachine was designed to image Cathepsin B activity alongside granzyme B during STING-activated immunotherapy, revealing high Cat B but low Gzm B activity in immune-suppressed tumor microenvironments and the opposite pattern in STING-activated tumors 41980121Apr. Another tumor-microenvironment-responsive nanosystem used overexpressed CTSB together with glutathione to drive in situ synthesis of a GPX4-degrading PROTAC, inducing ferroptosis and amplifying cuproptosis and photodynamic therapy-related reactive oxygen species generation 42114042May.

Beyond oncology and drug delivery, CTSB has appeared in disease biomarker and vaccine-related research. Integrative multi-omics implicated a CTSB/ITIH-ECM axis in autism spectrum disorder, suggesting a possible role for CTSB-linked extracellular matrix biology in neurodevelopmental pathology 42019823Apr. In temporal lobe epilepsy with hippocampal sclerosis, complement-associated microglial subpopulations were characterized using single-cell and spatial transcriptomics, and CTSB was among the complement-related genes examined in the broader biomarker framework 42458112Jul. In parasitology, Trichinella spiralis cathepsin B proteinase antigen formulated in nanoliposomes was evaluated as an immuno-protective vaccine candidate in murine trichinellosis 42169530May.

What Changes, What Holds

1. CTSB is being used as a drug-resistance and apoptosis-control node rather than only a degradative lysosomal protease
NEW DIRECTION Clomipramine’s effect in hepatocellular carcinoma frames cathepsin B as part of a lysosome-sequestration/autophagy resistance circuit that can be therapeutically manipulated to restore sorafenib activity 42377685Jun. Cepharanthine in triple-negative breast cancer also points to CTSB as a maturation-dependent vulnerability, but that finding mainly reinforces the established oncology relevance of CTSB while extending it into lysosomal maturation and TFEB-linked stress responses 42099230May.

2. CTSB inhibition is now implicated in immune-cell engineering and spinal cord repair, not just tumor biology and neurodegeneration
NEW DIRECTION Preventing trogocytosis and CAR T-cell fratricide adds a new functional role for cathepsin B in adoptive immunotherapy, with the practical implication that CTSB blockade may improve persistence rather than simply suppress proteolysis 42020353Apr. The spinal cord injury work likewise broadens CTSB into neuronal survival and repair biology, but it does not overturn the baseline; it instead suggests that CTSB/Ctsl inhibition can be neuroprotective in an acute injury context 42061005Apr.

3. CTSB is increasingly being exploited as a trigger and readout in engineered therapeutic platforms
METHOD The supramolecular fiber, DNAzyme nanomachine, and CTSB/glutathione-responsive nanosystem studies change how CTSB is used experimentally: as a stimulus, imaging signal, or assembly cue for controlled delivery and response mapping 41995357Apr41980121Apr42114042May. These are methodological extensions of the established enzyme-responsive delivery concept, not a revision of CTSB biology itself.

4. CTSB is emerging as a biomarker and vaccine antigen in non-oncologic settings, but these roles remain exploratory
NEW DIRECTION Multi-omics links to autism spectrum disorder and the epilepsy transcriptomic work place CTSB in disease-association frameworks the Overview does not cover, so they expand its possible relevance beyond lysosomes, cancer, and Parkinsonian models 42019823Apr42458112Jul. The Trichinella spiralis nanoliposome study similarly adds CTSB homologs as vaccine antigens, which is a new application rather than a challenge to the human CTSB account 42169530May.

Overview update candidates: CTSB as a modulator of CAR T-cell fratricide/persistence; CTSB-linked lysosomal sequestration and autophagy-related drug resistance in hepatocellular carcinoma; CTSB as a biomarker candidate in autism spectrum disorder and temporal lobe epilepsy; CTSB homologs as vaccine antigens in parasitology.