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Cathepsin B

Cathepsin B (CTSB) is a lysosomal cysteine protease belonging to the papain superfamily, encoded by the CTSB gene located on human chromosome 8p22-p23.1.^[1] It is synthesized as a preproenzyme consisting of 339 amino acids with a molecular weight of approximately 38 kDa, featuring a signal peptide, propeptide, and mature domain; this precursor undergoes glycosylation in the endoplasmic reticulum and Golgi apparatus before autocatalytic activation in the acidic lysosomal environment (pH ~4.5–5.0), yielding a mature enzyme of about 30–32 kDa that exhibits both endopeptidase and unique exopeptidase activities due to a flexible occluding loop (residues 105–122).^[2] Primarily localized to endolysosomes, Cathepsin B maintains cellular homeostasis by degrading intracellular proteins, processing antigens for MHC class II presentation, and activating prohormones and proenzymes, while its secretion via lysosomal exocytosis allows extracellular matrix (ECM) remodeling.^[1]^[3] In physiological contexts, Cathepsin B supports essential processes such as protein turnover and autophagy to recycle cellular components, bone resorption by degrading collagen in osteoclasts, and tissue remodeling during wound healing and embryonic development through ECM proteolysis of substrates like fibronectin, laminin, and collagen types I–IV.^[3] It also regulates immune responses by cleaving invariant chain for antigen loading and modulates apoptosis via caspase activation or mitochondrial targeting.^[1] Expression is ubiquitous across tissues, with higher levels in the spleen, lung, and placenta, and its activity is tightly controlled by endogenous inhibitors like cystatins and stefins, as well as pH-dependent mechanisms.^[3]^[2] Pathologically, Cathepsin B contributes to disease progression through aberrant overexpression, relocalization to the cytosol, cell surface, or extracellular space, and involvement in lysosomal membrane permeabilization (LMP).^[1] In cancer, it promotes tumor invasion, metastasis, and angiogenesis in malignancies such as breast, lung, colorectal, and pancreatic cancers by degrading ECM barriers and activating metalloproteinases, though it can exhibit a dual role by inducing apoptosis in some contexts to limit malignancy.^[3] In non-tumor diseases, it exacerbates neurodegeneration in Alzheimer's by generating neurotoxic amyloid-β fragments, drives atherosclerosis and myocardial infarction via vascular ECM degradation and inflammation, and facilitates kidney disorders through pyroptosis and ferroptosis in glomerular and tubular cells.^[1] Additionally, Cathepsin B activates the NLRP3 inflammasome in inflammatory conditions like obesity, diabetes, and emphysema, amplifying cytokine release and tissue damage.^[3] Given its pivotal roles, Cathepsin B is a promising biomarker for disease prognosis—elevated levels in serum or tissues correlate with poor outcomes in cancers and cardiovascular pathologies—and a therapeutic target, with selective inhibitors like nitroxoline and CA-074 showing potential to suppress tumor progression and inflammation without disrupting normal lysosomal function.^[3] Ongoing research focuses on its structural features, such as the occluding loop, to develop pH-specific inhibitors that exploit its activity differences in acidic lysosomes versus neutral extracellular environments.^[2]

Structure and Genetics

Gene

The CTSB gene, which encodes cathepsin B, is located on the short arm of human chromosome 8 at cytogenetic band 8p23.1 and consists of 14 exons spanning approximately 26 kb of genomic DNA.^[4] This organization includes 13 introns, with the gene oriented on the reverse strand from positions 11,842,524 to 11,868,087 in the GRCh38.p14 assembly.^[4] The promoter region upstream of the CTSB gene is characterized by a GC-rich sequence, exhibiting high GC content similar to housekeeping genes, and contains multiple binding sites for the transcription factor SP1, which play a key role in basal and inducible transcriptional regulation.^[5] These SP1 sites facilitate constitutive expression while allowing responsiveness to cellular signals, contributing to the gene's broad activity in lysosomal function.^[6] Alternative splicing of the CTSB pre-mRNA produces multiple transcript variants, with 13 reported in humans; the predominant variants (1–5 and 7–13) encode the full-length isoform 1 preproprotein of 339 amino acids (approximately 1,017 bp coding sequence), while variant 6 yields a shorter isoform 2 of 216 amino acids lacking the signal peptide.^[4] These variants exhibit tissue-specific expression patterns, with isoform 1 broadly distributed across most human tissues, showing highest levels in thyroid (RPKM 602.1) and appendix (RPKM 198.7), and lower but detectable expression in brain, liver, and immune cells.^[4] The CTSB gene demonstrates strong evolutionary conservation across mammals, reflecting its essential role in protein degradation; for instance, the mature cathepsin B protein shares about 82% amino acid sequence identity with its mouse ortholog and similarly high homology (around 80%) with the rat counterpart.^[7] This conservation extends to key functional domains, underscoring the gene's preservation through vertebrate evolution.^[8] In normal tissues, CTSB maintains moderate baseline expression to support lysosomal proteolysis, but it is upregulated in pathological conditions, particularly inflammatory states such as inflammatory bowel disease, where increased transcription in macrophages enhances immune responses and tissue remodeling.^[9] This upregulation is also observed in other inflammatory contexts, like psoriasis skin lesions, linking elevated CTSB levels to disease progression.^[10]

Protein Structure

Cathepsin B is synthesized as a preproenzyme consisting of 339 amino acids with a calculated molecular weight of approximately 37 kDa.^[11] This precursor includes an N-terminal signal peptide spanning residues 1–18, which directs the protein to the secretory pathway, followed by a propeptide region from residues 19–76 that maintains the enzyme in an inactive zymogen form.^[11] The mature protein domains begin after propeptide removal, encompassing the light chain (residues 81–126) and the heavy chain (residues 127–339).^[11] Maturation occurs through autocatalytic cleavage within the acidic environment of lysosomes, where the propeptide is first excised to generate a single-chain intermediate, followed by proteolytic separation into the two-chain mature form.^[12] The resulting light chain comprises approximately 46 amino acids with a molecular weight of about 5 kDa, while the heavy chain consists of 213 amino acids and has a molecular weight of 25–26 kDa. These chains are covalently linked by a disulfide bond, typically between cysteine residues in the light chain (Cys108) and heavy chain, stabilizing the dimeric structure essential for enzymatic function.^[11] The mature Cathepsin B adopts a papain-like fold characteristic of cysteine proteases, featuring two lobes that form a substrate-binding cleft with the active site at their interface.^[1] The catalytic triad, composed of Cys29 (nucleophile), His199 (base), and Asn219 (stabilizing the histidine), resides within this cleft and facilitates nucleophilic attack on peptide bonds. Unique to Cathepsin B among cysteine cathepsins is an occluding loop (residues 105–126 in mature numbering), a flexible ~20-residue insertion that partially obstructs the active site entrance, enabling dual endopeptidase and exopeptidase (specifically carboxydipeptidase) activities by restricting substrate access to C-terminal dipeptides.^[14] Crystal structures, such as the human mature form (PDB: 1HUC at 2.15 Å resolution) and bovine form (PDB: 1QDQ), reveal pH-dependent conformational dynamics in this loop, with histidine residues (His110, His111) protonating at acidic pH (optimal 5–6) to promote exopeptidase mode while shifting to endopeptidase at neutral pH.^[15]^[16] Post-translational modifications further refine Cathepsin B's structure and localization. The protein undergoes N-linked glycosylation primarily at Asn213 in the heavy chain, adding carbohydrate moieties that influence stability, trafficking, and observed molecular weight (often ~37–50 kDa on SDS-PAGE).^[11] Phosphorylation sites, such as at Ser80 and Thr201, have also been identified, potentially modulating activation and interactions, though their functional roles remain under investigation.^[11]

Biological Functions

Intracellular Roles

Cathepsin B serves as a primary lysosomal cysteine protease essential for intracellular protein degradation, where it facilitates the breakdown of long-lived proteins and autophagosomal contents to recycle amino acids and maintain cellular homeostasis.^[3] Within the acidic environment of lysosomes, concentrations of cathepsin B can reach up to 1 mM, enabling efficient proteolysis of diverse substrates and supporting metabolic processes across various cell types.^[3] This degradative function is crucial for endolysosomal turnover, preventing the accumulation of misfolded or damaged proteins that could otherwise disrupt cellular function.^[17] In immune cells such as dendritic cells and macrophages, cathepsin B contributes to antigen processing by cleaving internalized antigens and degrading the invariant chain (Ii) in endolysosomes, thereby facilitating peptide loading onto major histocompatibility complex class II (MHC II) molecules for presentation to T cells.^[3] Although studies in cathepsin B-deficient mice indicate that it is not strictly essential for MHC II-mediated antigen presentation, its activity influences the efficiency of Ii proteolysis and the selection of immunodominant epitopes during immune responses.^[18] This role underscores cathepsin B's involvement in adaptive immunity, particularly in professional antigen-presenting cells.^[19] Cathepsin B also regulates autophagy by processing substrates within autophagosomes and modulating lysosomal biogenesis through interactions with pathways involving transcription factor EB (TFEB) and mucolipin-1 (MCOLN1).^[20] Specifically, it degrades MCOLN1 to suppress TFEB activation, thereby limiting excessive autophagosome formation and ensuring balanced autophagic flux under homeostatic conditions.^[17] This regulatory mechanism helps prevent the buildup of damaged organelles and supports cellular adaptation to nutrient stress.^[3] During cellular stress, cathepsin B becomes activated upon lysosomal membrane permeabilization (LMP), allowing its release into the cytosol where it can cleave pro-apoptotic proteins like Bid, potentially initiating caspase-dependent apoptosis if not properly controlled.^[21] LMP-induced cathepsin B translocation serves as a checkpoint in the stress response, integrating lysosomal integrity with programmed cell death pathways to eliminate irreparably damaged cells.^[22] Among its specific intracellular substrates, cathepsin B processes fragments of the amyloid precursor protein (APP) within lysosomes, contributing to the degradation of amyloid-β peptides and thereby modulating proteostasis to avoid toxic aggregate formation.^[23] This activity highlights cathepsin B's role in neuroprotective protein handling, particularly in neuronal cells where APP metabolism influences synaptic function.^[24]

Extracellular Roles

Cathepsin B, originating from lysosomal compartments, is secreted extracellularly through mannose-6-phosphate-independent pathways involving alternative receptors such as sortilin, LRP1, and LDL receptor family members, which facilitate its targeting and export in various cell types including fibroblasts and hepatocytes.^[25]^[3] During inflammatory conditions, cathepsin B undergoes direct translocation via lysosomal exocytosis, a process triggered by cytokines and cellular stress that releases the enzyme into the extracellular milieu to modulate immune responses.^[3] Although exosomal export has been implicated in cathepsin secretion more broadly, cathepsin B primarily relies on these non-classical routes for extracellular delivery, enabling its participation in tissue-level proteolysis.^[3] In the extracellular space, cathepsin B plays a key role in degrading components of the extracellular matrix (ECM), cleaving proteins such as laminin, fibronectin, and type IV collagen to facilitate structural remodeling.^[26]^[27] This degradative activity extends to the activation of pro-forms of matrix metalloproteinases (MMPs), including MMP-2 and MMP-9, which amplifies ECM breakdown and supports dynamic tissue restructuring.^[28]^[29] Additionally, cathepsin B processes and activates other proteases, such as converting pro-urokinase plasminogen activator (pro-uPA) to its active form to promote fibrinolysis and initiating proteolysis cascades, while also contributing to the maturation of pro-cathepsin D in certain cellular contexts.^[3]^[30] Cathepsin B supports wound healing and inflammatory processes by degrading extracellular proteins, thereby aiding keratinocyte migration and fibroblast collagen regulation essential for tissue repair.^[31]^[32] In inflammatory settings, it contributes to the formation and function of neutrophil extracellular traps (NETs) through proteolytic modulation of associated proteins, enhancing pathogen clearance and immune activation.^[33] Unlike many lysosomal enzymes restricted to acidic environments, cathepsin B maintains stability and exhibits appreciable activity at neutral pH in extracellular spaces, allowing sustained function in physiological and pathological remodeling.^[34]^[35]

Role in Diseases

In Cancer

Cathepsin B is frequently overexpressed in various solid tumors, including those of the breast, lung, prostate, and colorectum, where elevated levels correlate with advanced disease stages and unfavorable patient outcomes. In breast cancer, upregulation of cathepsin B enhances tumor growth, invasion, and recurrence rates, serving as a prognostic indicator of poor survival. Similarly, in non-small cell lung cancer, higher cathepsin B expression is associated with reduced overall survival and increased metastatic potential. Prostate tumors exhibit cathepsin B amplification at chromosomal regions such as 8p22-23, contributing to invasive phenotypes, while in colorectal cancer, its overexpression promotes tumorigenesis and is linked to shortened patient survival and lymph node involvement. These patterns underscore cathepsin B's role as a biomarker of malignancy progression across these cancer types. Cathepsin B facilitates tumor invasion and metastasis primarily through extracellular matrix (ECM) remodeling and activation of proteolytic cascades. As a lysosomal cysteine protease, it degrades ECM components like laminin and collagen IV at the tumor-stromal interface, enabling cancer cell migration and tissue penetration. Additionally, cathepsin B activates the urokinase plasminogen activator (uPA)/plasmin system by converting pro-uPA to its active form, which in turn amplifies ECM breakdown and promotes pericellular proteolysis during metastatic dissemination. This mechanism is particularly evident in breast and colorectal cancers, where cathepsin B's activity at the invasive front correlates with enhanced tumor cell motility and distant spread. In supporting tumor angiogenesis, cathepsin B modulates vascular endothelial growth factor (VEGF) signaling and processes basement membrane proteoglycans to liberate pro-angiogenic factors. It regulates the angiogenic threshold in endothelial cells by influencing VEGF-dependent tube formation, with suppression of cathepsin B reducing neovascularization in tumor models. Furthermore, cathepsin B contributes to the cleavage of perlecan, releasing fragments that promote endothelial cell proliferation and vessel sprouting, thereby sustaining nutrient supply to hypoxic tumors. These actions are critical in gliomas and breast cancers, where cathepsin B inhibition impairs VEGF-mediated angiogenesis. Cathepsin B confers resistance to apoptosis in tumor cells, particularly under cellular stress, by lysosomal leakage and interference with caspase activation. Intracellular relocation of cathepsin B allows it to cleave and inhibit pro-apoptotic caspases, such as caspase-3 and -9, thereby preventing programmed cell death and promoting survival in harsh tumor microenvironments. This anti-apoptotic function is observed in lung and prostate cancers, where elevated cathepsin B levels protect cells from chemotherapy-induced apoptosis, contributing to treatment resistance. Recent investigations post-2023 have highlighted cathepsin B's involvement in urological malignancies, such as bladder cancer, where it drives epithelial-mesenchymal transition (EMT) by upregulating vimentin and enhancing invasive properties in orthotopic models. In these contexts, cathepsin B overexpression correlates with increased tumor aggressiveness and potential for metastasis. Therapeutically, targeting cathepsin B in combination with immunotherapy shows promise; for instance, cathepsin B inhibitors augment CAR T-cell efficacy by preventing trogocytosis and enhancing antitumor immunity. These findings suggest combined strategies could improve outcomes in immunotherapy-resistant cancers.^[36]

In Neurodegenerative and Other Diseases

Cathepsin B exhibits a dual role in Alzheimer's disease, where it degrades amyloid-β (Aβ) peptides, particularly the fibrillogenic Aβ1-42 isoform, to reduce plaque formation and associated neuronal toxicity, but also generates neurotoxic truncated Aβ fragments that exacerbate neurodegeneration. Studies in mouse models expressing wild-type human amyloid precursor protein have demonstrated that cathepsin B cleaves Aβ, limiting its aggregation and accumulation in the brain.^[37] Genetic knockout of cathepsin B in these models impairs Aβ clearance, exacerbating plaque load and worsening memory deficits, highlighting its role in lysosomal degradation pathways.^[38] Furthermore, while elevated cathepsin B activity can correlate with reduced Aβ1-x levels, it also contributes to production of harmful forms like Aβ2-x in certain cellular contexts.^[39] In Parkinson's disease and other neurodegenerative conditions, cathepsin B contributes to the processing and clearance of alpha-synuclein aggregates, key pathological hallmarks of the disorder.^[40] As a lysosomal protease, it facilitates the breakdown of fibrillar alpha-synuclein, promoting its removal from neurons and mitigating Lewy body formation.^[41] Cathepsin B also influences neuroinflammation by activating microglia, where its release from lysosomes triggers inflammatory signaling that can exacerbate neuronal damage in chronic neurodegeneration.^[42] In microglial cells, cathepsin B modulates phagocytosis of aggregates while contributing to cytokine production, illustrating its dual involvement in both protective clearance and pathological inflammation.^[43] In kidney diseases, cathepsin B induces programmed cell death pathways, including ferroptosis and pyroptosis, driving tissue injury in conditions such as acute kidney injury (AKI) and diabetic nephropathy.^[44] During AKI, lysosomal rupture releases cathepsin B, which activates lipid peroxidation and iron-dependent ferroptosis in renal tubular cells, amplifying oxidative damage and inflammation.^[45] In diabetic nephropathy, upregulated cathepsin B promotes pyroptosis via NLRP3 inflammasome activation, leading to gasdermin D-mediated pore formation and cytokine release that exacerbates glomerular fibrosis and podocyte loss.^[44] Inhibition of cathepsin B in experimental models reduces these cell death mechanisms, preserving renal function and highlighting its pro-pathogenic role. In cardiovascular diseases, cathepsin B contributes to atherosclerosis by degrading extracellular matrix components, such as elastin and collagen, which destabilizes atherosclerotic plaques and increases rupture risk.^[46] Macrophage-derived cathepsin B in plaques enhances matrix metalloproteinase activity, promoting thinning of the fibrous cap and inflammatory cell infiltration.^[47] Conversely, cathepsin B exhibits protective effects in cardiac remodeling following myocardial injury, where it aids in the clearance of damaged myocardium and facilitates adaptive extracellular matrix turnover to prevent excessive fibrosis.^[48] In post-infarction models, balanced cathepsin B activity supports ventricular repair by degrading necrotic debris without overactivating inflammatory cascades.^[49] Recent post-2023 findings have implicated cathepsin B in hemodialysis-related amyloidosis, where it fragments and destroys β2-microglobulin amyloids, preventing cytotoxic aggregate accumulation in osteoarticular tissues of dialysis patients.^[50] In immune-mediated inflammatory diseases like rheumatoid arthritis, cathepsin B displays dual roles: it drives pathological synovial degradation and fibroblast-like synoviocyte invasion via extracellular matrix breakdown, yet also participates in antigen processing for adaptive immune responses that may limit chronic inflammation.^[51]^[52] These insights underscore cathepsin B's context-dependent functions in non-cancer pathologies, with implications for targeted modulation in disease management.^[53]

Regulation and Interactions

Protein-Protein Interactions

Cathepsin B interacts with the annexin II tetramer on the surface of tumor cells, where procathepsin B binds to the heterotetramer complex consisting of two p11 and two p36 subunits, promoting its extracellular retention and maturation into active enzyme.^[54] This binding facilitates the localization of cathepsin B to the cell surface, enabling it to activate urokinase-type plasminogen activator (uPA) and support pericellular proteolysis essential for tumor cell invasion and migration.^[55] Cathepsin B associates with chondroitin sulfate proteoglycans (CSPGs) in the extracellular matrix, where it contributes to their degradation, thereby modulating its own proteolytic activity in cartilage and tumor microenvironments. In cartilage, this interaction supports the cleavage of aggrecan, a major CSPG, at specific sites such as Asn341-Phe342, influencing matrix remodeling during physiological and pathological processes like osteoarthritis. In tumor settings, cathepsin B-mediated degradation of CSPGs alters the extracellular environment, enhancing tumor cell motility and invasion without direct inhibitory binding observed for other glycosaminoglycans.^[56] Within lysosomes, cathepsin B associates with MHC class II molecules, participating in the proteolytic degradation of the invariant chain (Ii) to generate the CLIP fragment, which is subsequently exchanged for antigenic peptides to facilitate antigen presentation.^[57] Although cathepsins S and L play dominant roles in later Ii processing steps, cathepsin B's endopeptidase activity is essential for initial cleavages, ensuring efficient MHC class II maturation in antigen-presenting cells.^[58] Cathepsin B forms functional complexes with other cathepsins, such as cathepsin L, in multienzyme cascades that enable cooperative proteolysis of substrates in lysosomal and extracellular compartments.^[59] These interactions allow sequential or compensatory degradation, as evidenced by the severe phenotype in double-knockout models where loss of both enzymes impairs protein turnover and leads to early postnatal lethality. Recent investigations highlight cathepsin B's interactions with amyloid proteins in neurodegenerative contexts, where it fragments amyloid-β (Aβ) peptides and α-synuclein aggregates, promoting their clearance and mitigating neurotoxicity.^[60] For instance, cathepsin B cleaves Aβ1-42 into non-toxic fragments, reducing plaque formation in Alzheimer's disease models, while also degrading α-synuclein fibrils to prevent Lewy body accumulation in Parkinson's disease.^[50] These proteolytic actions underscore cathepsin B's role in lysosomal autophagy pathways for amyloid protein homeostasis.^[61]

Inhibitors and Regulation

Cathepsin B activity is tightly controlled by endogenous inhibitors, primarily members of the cystatin superfamily, which bind to its active site to prevent uncontrolled proteolysis. Cystatins, such as cystatin C, form tight complexes with the enzyme's catalytic cysteine residue, exhibiting inhibition constants (Ki) in the range of approximately 0.1-1 nM, thereby modulating lysosomal and extracellular degradation processes. Stefins, including stefin A and stefin B, serve as intracellular regulators, localizing to the cytosol and nucleus where they inhibit cathepsin B and related cysteine proteases to maintain cellular homeostasis.^[62]^[63]^[64] The enzyme's activity is also profoundly influenced by environmental factors, particularly pH and redox conditions. Cathepsin B exhibits optimal proteolytic function in acidic environments (pH 4.5-6.0) typical of lysosomes, where it adopts an endopeptidase conformation, while at neutral pH it shifts toward exopeptidase activity. A reducing milieu, maintained by glutathione, is essential for preserving the active-site cysteine (Cys29) in its reduced thiol form; oxidation of Cys29, often induced by reactive oxygen species or lipid peroxidation products like 4-hydroxynonenal, leads to irreversible inactivation through adduct formation.^[65]^[34]^[66] At the transcriptional level, cathepsin B expression is upregulated by the transcription factor NF-κB during inflammatory responses, enhancing lysosomal capacity in immune cells. Negative feedback is provided by microRNAs, such as miR-185, which directly targets CTSB mRNA to suppress its translation and limit excessive protease production.^[67]^[68]^[69] Post-translational regulation involves the processing of the inactive zymogen procathepsin B, which undergoes autocatalytic removal of its N-terminal propeptide in a pH-dependent manner to generate the mature enzyme. The propeptide not only inhibits activity during synthesis and trafficking but also contributes to zymogen stability, preventing premature activation in the endoplasmic reticulum or Golgi apparatus.^[12]^[70] Synthetic inhibitors have been developed to mimic and enhance these regulatory mechanisms. Epoxysuccinyl peptides, such as CA-074, act as irreversible inhibitors by covalently binding the active-site cysteine, achieving an IC50 of approximately 1 nM under lysosomal conditions. More recently, reversible inhibitors analogous to odanacatib, a nitrile-based compound originally targeting cathepsin K, have shown promise for selective cathepsin B inhibition through non-covalent interactions with the active site.^[71]^[72]^[73]

Therapeutic Potential

Inhibitors as Therapeutics

Pharmacological inhibition of Cathepsin B has emerged as a promising strategy for treating cancers where the enzyme is overexpressed and contributes to tumor progression, invasion, and metastasis. In preclinical models, the selective Cathepsin B inhibitor CA-074 and its derivatives, such as CA-074Me, have demonstrated significant reduction in tumor invasion and bone metastasis. For instance, administration of CA-074 in breast cancer mouse models limited pulmonary and bone metastasis by impairing extracellular matrix degradation and tumor cell migration.^[74]^[75] These inhibitors exhibit high potency against Cathepsin B (Ki = 2-5 nM) with selectivity over other cathepsins like H and L.^[76] Combining Cathepsin B inhibition with chemotherapy has shown enhanced efficacy in preclinical studies. For example, pairing cathepsin inhibitors with paclitaxel (Taxol) reduced tumor-associated macrophage activity and improved outcomes against primary and metastatic tumors by blunting chemotherapeutic responses mediated by extracellular cathepsins.^[77] This synergy arises from Cathepsin B's role in promoting tumor microenvironment remodeling, which can confer resistance to standard chemotherapies.^[5] Despite preclinical success, clinical translation of Cathepsin B inhibitors remains limited. No Cathepsin B-specific inhibitors have advanced to clinical trials for cancer as of 2025, though broad-spectrum cysteine cathepsin inhibitors have been explored in early-phase studies for related conditions, often halted due to off-target effects such as musculoskeletal toxicity.^[78] These challenges highlight the need for improved selectivity to avoid inhibiting other lysosomal cathepsins. Key hurdles in developing Cathepsin B inhibitors include achieving specificity to prevent lysosomal dysfunction, which can impair autophagy and lead to cellular toxicity. Inhibition of Cathepsin B alongside other cathepsins like L disrupts lysosomal proteolysis, resulting in accumulation of undigested substrates and exacerbated cell death in non-tumor cells.^[79] Post-2023 advancements have focused on B-selective inhibitors, such as neutral pH-active compounds targeting cytosolic Cathepsin B and repurposed drugs like lurasidone and paliperidone, which show promise for overcoming pH-dependent limitations in tumor environments.^[80]^[81] Emerging approaches emphasize targeted delivery to enhance tumor specificity and minimize systemic effects. Nanoparticle-based systems and prodrug designs responsive to tumor conditions are being developed to deliver Cathepsin B inhibitors selectively to cancer sites, potentially integrating with antibody-drug conjugates for precision oncology.^[82] Additionally, proteolysis-targeting chimeras (PROTACs) activated in the tumor microenvironment offer a novel avenue for degrading hyperactive Cathepsin B, though current designs often leverage the enzyme for activation rather than direct targeting.^[83] The dual role of Cathepsin B necessitates context-specific therapeutic strategies. While inhibition benefits cancer treatment by curbing invasion, it may exacerbate amyloid-β buildup in Alzheimer's disease, as Cathepsin B normally degrades amyloid peptides; thus, indiscriminate inhibition could worsen neurodegeneration.^[84] Conversely, strategies to enhance Cathepsin B activity show promise for Alzheimer's; as of November 2025, preclinical muscle-driven gene therapy increasing Cathepsin B production as a myokine has demonstrated potential to protect memory function in Alzheimer's models by promoting neurogenesis and reducing amyloid pathology.^[85]

Biomarkers and Diagnostic Applications

Cathepsin B (CTSB) has emerged as a promising biomarker in serum and plasma for various cancers, where elevated levels often correlate with disease progression and staging. In ovarian cancer patients, serum procathepsin B concentrations are significantly increased compared to healthy controls and those with benign tumors, with approximately a 1.8-fold elevation relative to the benign group (p<0.001), aiding in differential diagnosis when combined with standard markers like CA-125.^[86] Similarly, in nasopharyngeal carcinoma, serum CTSB levels show diagnostic utility, with higher concentrations distinguishing affected patients from controls, though prognostic value remains limited.^[87] For metastatic breast cancer, while specific fold changes vary, elevated serum CTSB is associated with poor outcomes and lymph node involvement, supporting its role in staging advanced disease.^[88] Tissue expression of CTSB, assessed via immunohistochemistry (IHC), provides prognostic insights in multiple tumor types by correlating with invasion and survival. In non-small cell lung cancer, higher IHC scores for CTSB expression are significantly linked to shorter overall survival (p<0.01), independent of other factors, and predict lymph node metastasis.^[89] In colon cancer, strong CTSB staining in tumor cells is prevalent across stages and associates with reduced disease-free survival in multivariate models.^[90] These patterns extend to brain tumors, where total CTSB IHC scores exceeding 8 indicate poorer prognosis in glioblastoma (p=0.003).^[91] Advanced imaging probes targeting CTSB enable non-invasive tumor detection, particularly in preclinical settings. Near-infrared fluorescent probes activated by CTSB, such as those designed for protease imaging, achieve high tumor-to-background ratios (100-300% fluorescence increase) and detect lesions as small as 50 μm in colon and breast cancer models.^[92] These probes facilitate intraoperative visualization, with cathepsin B-specific activation enhancing specificity for metastatic sites in murine studies.^[93] Beyond oncology, CTSB serves as a biomarker in non-cancerous conditions, including kidney injury and neurodegenerative diseases. Urinary CTSB activity rises in acute kidney injury (AKI), reflecting tubular damage and serving as an early indicator alongside other lysosomal enzymes, with elevated levels correlating to severity in experimental models.^[94] In Alzheimer's disease, cerebrospinal fluid (CSF) levels of CTSB in extracellular vesicles negatively correlate with amyloid-β42 concentrations, supporting its potential for early diagnosis and monitoring neurodegeneration.^[95] Recent advances highlight CTSB's integration into multi-omics frameworks for enhanced diagnostic precision. Post-2023 studies have incorporated CTSB profiling in AI-driven multi-omics analyses of cardiovascular risk, where elevated CTSB in plasma and tissue omics data predicts atherosclerosis progression when combined with genomic and proteomic signatures.^[96] Additionally, exosomal CTSB emerges as a liquid biopsy marker, with upregulated levels in urinary exosomes from bladder cancer patients and plasma exosomes aiding non-small cell lung cancer staging, offering minimally invasive monitoring.^[97]^[98]

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[27]
Intracellular and extracellular cathepsin B facilitate invasion of MCF ...
The proteolytic activity of cathepsin B has been suggested to facilitate direct degradation of ECM proteins, including fibronectin, type I and type IV collagen, ...
[28]
Increased gelatinase A (MMP-2) and cathepsin B activity in invasive ...
Gelatinase A (MMP-2) and cathepsin B are proteinases which have been proposed to participate in human tumor invasion and metastasis.
[29]
Cathepsin B Is Upregulated and Mediates ECM Degradation in ...
MMP-14, a membrane-associated enzyme that has the ability to activate other MMPs, such as MMP-2, from their inactive isoforms as well as to degrade collagen, ...
[30]
Relationship between cathepsin D, urokinase, and plasminogen ...
When Cath D, uPA, PAI-1 and PAI-2 levels in malignant tumours were compared, positive correlations were found for all combinations. The implication of ...
[31]
Cathepsin B is essential for regeneration of scratch-wounded ...
Migration, proliferation and differentiation of keratinocytes are important processes during tissue regeneration and wound healing of the skin.Missing: repair | Show results with:repair
[32]
Cathepsin B Regulates Collagen Expression by Fibroblasts via ...
Fibroblasts are essential for tissue repair due to producing collagens, and lysosomal proteinase cathepsin B (CatB) is involved in promoting chronic ...
[33]
Neutrophil extracellular traps (NETs): Double-edged swords ... - PMC
NETs participate in pathogenesis of autoimmune and inflammatory disorders, with proposed involvement in glomerulonephritis, chronic lung disease, sepsis and ...
[34]
Cathepsin B in programmed cell death machinery - Nature
Apr 8, 2023 · Herein, we will review and discuss the role of CatB in PCD during disease progression (Table 1). Fig. 7: Cathepsin B in diseases. figure 7.
[35]
Quantitative Detection of Cathepsin B Activity in Neutral pH Buffers ...
Sep 21, 2021 · This study demonstrates an activity-based electrochemical biosensor of a 3 × 3 gold microelectrode array for the detection of cathepsin B activity in human ...Experimental Section · Results and Discussion · Conclusions · References
[36]
Cathepsin B degrades amyloid-β in mice expressing wild ... - PubMed
Nov 16, 2012 · We showed that the cysteine protease cathepsin B (CatB) degrades Aβ, most likely by C-terminal truncation, in mice expressing human amyloid precursor protein.
[37]
Cathepsins in Neurological Diseases - MDPI
Evidence shows that cathepsin B gene CTSB knockout decreased neuronal granule cell damage in mice models [129]. Removal of cathepsins L and S in cystatin B- ...
[38]
The Role of Cathepsin B in the Degradation of Aβ and in ... - PubMed
Jan 12, 2021 · These findings highlight the importance of considering organelle targeting in drug development to promote Aβ degradation. Keywords: Alzheimer's ...
[39]
The Parkinson's disease risk gene cathepsin B promotes fibrillar ...
Nov 25, 2024 · The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity ...
[40]
Cysteine cathepsins are essential in lysosomal degradation of α ...
Jul 28, 2015 · This work implicates CtsB and CtsL as essential in α-syn lysosomal degradation, establishing groundwork to explore mechanisms to enhance their cellular ...
[41]
Microglial cathepsin B as a key driver of inflammatory brain diseases ...
Microglial cathepsin B could function as a major driver for inflammatory brain diseases and brain aging.
[42]
Cathepsin regulation on microglial function - PubMed
Jun 9, 2020 · Increased expression and secretion of various cathepsins support roles of activated microglia in chronic neuroinflammation, the neurotoxic M1- ...
[43]
Cathepsin B induces kidney diseases through different types of ...
Ferroptosis also plays a key role in kidney diseases such as acute kidney injury ... renal ischemia/reperfusion injury by inhibiting cathepsin mediated ...
[44]
Cathepsin B is an executioner of ferroptosis - ScienceDirect.com
Our work identifies new and yet-unrecognized aspects of ferroptosis and identifies cathepsin B as a mediator of ferroptotic cell death.Missing: kidney | Show results with:kidney
[45]
The function of cathepsins B, D, and X in atherosclerosis - PMC - NIH
Furthermore, cathepsin D regulates apoptosis. Cathepsin B degrades the extracellular matrix within the arterial intima. Together, they increase plaque ...
[46]
Cysteine Protease Cathepsins in Atherosclerosis-Based Vascular ...
Oct 10, 2011 · Angiotensin inhibition decreased the progression of advanced atherosclerosis and improved plaque instability by inhibition of the mRNA and ...
[47]
Role for Cysteine Protease Cathepsins in Heart Disease | Circulation
Mar 27, 2012 · It has been shown that cathepsin B protein levels and activity in cardiac tissues change in response to injury. To our surprise, the data ...
[48]
Cathepsin B deficiency attenuates cardiac remodeling in ... - PubMed
May 1, 2015 · Cathepsin B deficiency attenuates cardiac remodeling in response to pressure overload via TNF-α/ASK1/JNK pathway · Authors · Affiliations.
[49]
Cathepsin B prevents cell death by fragmentation and destruction of ...
Feb 15, 2025 · This study investigates the impact of cysteine protease cathepsin B (CTSB) on amyloids associated with Alzheimer's and Parkinson's diseases, hemodialysis, and ...Missing: post- | Show results with:post-
[50]
Cathepsin B serves as a potential prognostic biomarker and ...
Feb 15, 2024 · This study identified CTSB, a gene associated with ferroptosis, as a potential biomarker for diagnosing and managing RA.Missing: dual post-
[51]
The multifaceted roles of cathepsins in immune and inflammatory ...
Dec 31, 2024 · Cathepsins are lysosomal proteases involved in protein degradation, antigen presentation, apoptosis, tissue remodeling, and regulating immune ...
[52]
A radioactive and fluorescent dual modality cysteine cathepsin-B ...
Aug 25, 2024 · This study aims to evaluate an activity-based multi-modality diagnostic agent, 68Ga-BMX2, which targets CTS-B to visualize the arthritis ...Missing: roles | Show results with:roles
[53]
Human procathepsin B interacts with the annexin II tetramer on the ...
Apr 28, 2000 · Our results indicate that the annexin II tetramer can serve as a binding protein for procathepsin B on the surface of tumor cells.
[54]
Cell Surface Complex of Cathepsin B/annexin II Tetramer ... - PubMed
Mar 7, 2000 · Recently, we demonstrated that procathepsin B interacts with the annexin II heterotetramer (AIIt) on the surface of tumor cells. AIIt had ...
[55]
Cysteine Cathepsins and Their Extracellular Roles - MDPI
Pathological collagen degradation is connected with cathepsin K overexpression and unbalanced osteoclast/osteoblast activation, leading to collagen I ...
[56]
Lysosomal cathepsin B plays an important role in antigen ... - NIH
Both cathepsin B and cathepsin D are necessary for processing of ovalbumin as well as for degradation of class II MHC invariant chain. Immunol Lett. 1994;43 ...
[57]
Double deficiency of cathepsins B and L results in ... - PubMed
Jun 29, 2013 · Endolysosomal cysteine cathepsins functionally cooperate. Cathepsin B (Ctsb) and L (Ctsl) double-knockout mice die 4 weeks after birth ...
[58]
Cathepsin B in Neurodegeneration of Alzheimer's Disease ...
Knockout (KO) of the cathepsin B gene (CTSB) results in alleviation of memory deficits in animal models of AD (75), PgLPS (72), and aging (73), and improvement ...Missing: worsens | Show results with:worsens
[59]
Recombinant cathepsins B and L promote α-synuclein clearance ...
Aug 29, 2025 · The cysteine proteases cathepsin B (CTSB) and cathepsin L (CTSL) are involved in the clearance of various neurodegenerative disease-related ...
[60]
Stefin A displaces the occluding loop of cathepsin B only by as much ...
Aug 24, 2010 · Cathepsin B differs from other cathepsins by its dual role, exhibiting exo- as well as endopeptidase activity. The crystal structure of this ...Abstract · Introduction · Results and Discussion · Materials and methods
[61]
Stefin B Interacts with Histones and Cathepsin L in the Nucleus
Stefin B could thus play an important role in regulating the proteolytic activity of cathepsin L in the nucleus, protecting substrates such as transcription ...
[62]
Cathepsins and their endogenous inhibitors cystatins: expression ...
In the present study, we evaluated whether expression levels of cathepsins S and B and their inhibitors cystatins B and C are affected by multiple sclerosis ( ...
[63]
Selective Neutral pH Inhibitor of Cathepsin B Designed Based on ...
Aug 20, 2021 · Cathepsin B is active at both the neutral pH 7.2 of the cytosol and the acidic pH 4.6 within lysosomes. We evaluated the hypothesis that ...
[64]
Hydroxynonenal inactivates cathepsin B by forming Michael adducts ...
This report shows that the lysosomal protease cathepsin B can be inactivated by the lipid peroxidation product 4-hydroxy-2-nonenal (HNE). Oxidation of LDL leads ...
[65]
Article Nuclear Factor-κB Mediates Up-Regulation of Cathepsin B by ...
In the cathepsin B gene promoter region, a potential nuclear factor κB (NF-κB) binding site could be identified. Pretreatment of HeLa cells with specific NF-κB ...
[66]
Nuclear Factor-κB Mediates Up-Regulation of Cathepsin B by ...
In summary, our data clearly indicate that anthracyclines induce cathepsin B via NF-κB. The data contribute to a better understanding of tumor targeting ...
[67]
Functional lncRNA-miRNA-mRNA networks in rabbit carotid ...
We also found that XLOC_062719 and XLOC_063297 were ceRNAs of ocu-miR-185-3p targeting CTSB, CTSS and EDNRA. Inflammation and angiogenesis broadly interact by ...
[68]
Molecular Insight into Propeptide–Protein Interactions in Cathepsins ...
Cathepsin B and other lysosomal cysteine proteinases are synthesized as inactive zymogens, which are converted to their mature forms by other proteases or ...
[69]
https://pmc.ncbi.nlm.nih.gov/articles/PMC7041763/
[70]
Molecular Features of CA-074 pH-Dependent Inhibition of Cathepsin B
Feb 4, 2022 · Mature human and bovine cathepsin B share 88.3% protein sequence identity and 100% sequence identity for the amino acids (His 110 and His111) ...
[71]
Cathepsin B Inhibitors for Targeted Cancer Therapy
Sep 29, 2014 · Drugs already successful in clinical trials to treat other conditions unrelated to cathepsin B, such as osteoporosis with odanacatib, ...
[72]
Cathepsin B Inhibition Limits Bone Metastasis in Breast Cancer
Similarly, intraperitoneal administration of the highly selective cathepsin B inhibitor CA-074 reduced metastasis in tumor-bearing animals, a reduction that ...
[73]
Cathepsin B inhibition interferes with metastatic potential of human ...
Aug 4, 2010 · We found that, unlike cathepsins D and L, the inhibition of cathepsin B significantly impaired cell invasiveness and metastatic potential.
[74]
CA 074 | Cathepsin - Tocris Bioscience
CA 074 is an inhibitor of cathepsin B (Ki = 2-5 nM). Displays selectivity over cathepsins H and L (Ki = 40-200 μM). Shown to reduce bone metastasis in a 4T1 ...Missing: therapeutics | Show results with:therapeutics
[75]
Macrophages and cathepsin proteases blunt chemotherapeutic ...
Combining Taxol with cathepsin inhibition in vivo significantly enhanced efficacy against primary and metastatic tumors, supporting the therapeutic relevance ...
[76]
Study of Cathepsin B inhibition in VEGFR TKI treated human renal ...
Feb 22, 2019 · To our knowledge, there are currently no CTSB inhibitors in clinical trials. Our results open a pathway for potential development of novel CTSB ...
[77]
Cathepsin Inhibition-Induced Lysosomal Dysfunction Enhances ...
Our findings suggest that cathepsin defects following the inhibition of cathepsin B and L result in lysosomal dysfunction and consequent cell death in ...
[78]
Neutral pH-Selective Inhibition of Cytosolic Cathepsin B: A Novel ...
Jul 23, 2025 · After TBI, cathepsin B becomes more diffusely localized in the cortical cells, consistent with its increased cytosolic subcellular distribution.Missing: post- | Show results with:post-
[79]
Unveiling Cathepsin B inhibition with repurposed drugs for ...
This elevated CatB activity correlates with poor therapy outcomes that emphasize its relevance as a promising therapeutic target for cancer as well [17].
[80]
Smart Delivery Systems Responsive to Cathepsin B Activity for ...
Jun 29, 2023 · The cleavage of the signal peptide (SP) results in the formation of procathepsin B, which is transferred to the Golgi apparatus and finally to ...2. Cathepsin B Synthesis And... · 4. Ctsb-Responsive Delivery... · 4.1. Ctsb-Sensitive...Missing: autocatalytic | Show results with:autocatalytic<|separator|>
[81]
Sequential responsive nano-PROTACs for precise intracellular ...
Oct 18, 2024 · After internalization by tumor cells, PROTAC were released intracellularly by cleavage of cathepsin B in lysosomes. Herein, PSRNs had ...
[82]
Evaluation of serum procathepsin B, cystatin B and ... - PubMed
Aug 5, 2013 · In the ovarian cancer group, both levels of serum procathepsin B and standard biomarker CA-125 increased significantly (both p<0.001) ...
[83]
Diagnostic Values of Serum Cathepsin B and D in Patients With ...
Mar 19, 2016 · Serum CTSB and CTSD concentrations were found to have a diagnostic value in NPC. However, the CTSB and CTSD serum levels had no prognostic ...
[84]
High Levels of Cathepsin B Predict Poor Outcome in Patients With ...
High Levels of Cathepsin B Predict Poor Outcome in Patients With Breast Cancer ... cancer metastasis, correlates with poor outcome in patients with breast cancer.Missing: serum | Show results with:serum
[85]
Immunohistochemical study of cathepsin B. Prognostic significance ...
Jul 1, 1994 · Results. Higher grade expression of cathepsin B was associated significantly with shorter survival in nonsmall cell lung cancer (P < 0.01), in ...
[86]
Cathepsin B Expression and Survival in Colon Cancer
Among 558 participants, 457 (82%) had tumors that expressed cathepsin B ... Expression of cathepsin B and cystatin C in human colorectal cancer. Hum ...
[87]
Cathepsin B Staining: New Prognostic Factor for Brain Tumor Survival
Univariate survival analysis indicated that total Cat B score above 8 was a significant predictor for shorter overall survival (P = 0.003). In glioblastoma ...
[88]
Near-Infrared Optical Imaging of Proteases in Cancer - AACR Journals
The cathepsin B probe helped detect lesions as small as 50 μm in diameter, based on an increase in fluorescence of 100–300% compared with background tissue. Fig ...
[89]
Optical Imaging with a Cathepsin B Activated Probe ... - Theranostics
Near Infrared (NIR) optical imaging combined with fluorescent probes has been applied towards more sensitive detection of a range of cancers including colon, ...
[90]
[PDF] Biomarkers For Acute Kidney Injury
... biomarkers are related to functional injury (cystatin C; total protein; albumin; β-2 microglobulin; urinary enzymes, such as NAG, cathepsin B, and β ...
[91]
Extracellular vesicle proteome unveils cathepsin B connection to ...
Dec 10, 2023 · The CSF and plasma EV CatB levels showed a negative correlation with CSF amyloid-β42 concentrations. This proteomic landscape of CSF EVs in ATN ...Abstract · Materials and methods · Results · Discussion
[92]
Cathepsin B in cardiovascular disease: Underlying mechanisms and ...
Sep 9, 2024 · Hence, the expression levels of CTSB in both cardiac tissue and circulation may play a crucial role in the onset and progression of HF.
[93]
Exosome, the glass slipper for Cinderella of cancer—bladder cancer?
Oct 7, 2023 · According to Xinyuan Li, cathepsin B (CTSB) was upregulated in exosomes ... exosomes treated as diagnostic biomarker for bladder cancer.
[94]
Early detection of non-small cell lung cancer in liquid biopsies by ...
Aug 7, 2020 · Although cathepsin B was unsuited for detecting (sub)stage 1 NSCLC, it provides data for cancer staging via liquid biopsy. In opposite to ...