Cathepsin B

Cathepsin B (CTSB) is an exercise-induced lysosomal cysteine protease and myokine that crosses the blood–brain barrier to promote hippocampal neurogenesis and cognitive function by upregulating neurotrophic factors like BDNF and doublecortin PMID 40818821PMID 39456173PMID 38393277. While primarily investigated for its neuroprotective ability to reduce amyloid-β plaque load in Alzheimer's disease, CTSB exhibits a complex therapeutic profile that includes inducing ferroptosis in pancreatic cancer cells and potentially mediating neuroinflammation under specific pathological conditions PMID 39988270PMID 36118704PMID 35283168.

• Proteolytic and Lysosomal Activity: CTSB is primarily involved in the degradation of misfolded or accumulated intracellular proteins to maintain cellular homeostasis PMID 40818821. In skeletal muscle, it acts as a catabolic enzyme that facilitates the repair of damaged muscle tissue following exercise PMID 39456173.
• Neurotrophic Signaling: After crossing into the central nervous system, CTSB upregulates the expression of Brain-Derived Neurotrophic Factor (BDNF) and doublecortin (DCX). This upregulation occurs via a p11-dependent mechanism and is critical for hippocampal neurogenesis, neuronal migration, and dendritic spine structural plasticity PMID 39988270PMID 40818821PMID 38393277.
• Amyloid Processing: CTSB exhibits anti-amyloidogenic activity by proteolytically cleaving Amyloid Precursor Protein (APP) into peptides with lower amyloidogenic potential, thereby reducing Amyloid-β (Aβ) plaque deposition PMID 36118704.
• Ferroptosis Induction: In specific pathological contexts like pancreatic cancer, nuclear accumulation of CTSB activates the STING1 pathway, triggering DNA damage and inducing ferroptosis (iron-dependent cell death) PMID 39988270.

CTSB is classified as a myokine and exerkine because its secretion into the circulation is stimulated by physical activity, allowing it to mediate crosstalk between skeletal muscle and the brain.

• Exercise-Induced Secretion: Acute and chronic exercise (particularly aerobic training) stimulates the production and release of CTSB from skeletal muscle PMID 40869331PMID 38393277. This release is regulated by metabolic sensors such as AMPK and mTOR pathways activated by mechanical stress and metabolic activity PMID 40818821.
• Blood-Brain Barrier (BBB) Permeability: A defining characteristic of CTSB as a neuroprotective exerkine is its ability to cross the blood–brain barrier. This allows muscle-derived CTSB to directly influence hippocampal function, serving as a physical link in the muscle–brain axis PMID 39988270PMID 40801027PMID 39456173.
• Correlation with Performance: In humans, circulating CTSB levels correlate positively with hippocampus-dependent memory performance and aerobic fitness PMID 40818821PMID 37395284.

• Cognitive Enhancement & Alzheimer’s Disease (AD): CTSB is a potential therapeutic target for mitigating memory deficits and AD pathology. By promoting Aβ clearance, CTSB helps restore lysosomal function and enhance hippocampal neurogenesis PMID 38393277PMID 36118704.
• Cancer Therapy: Due to its ability to induce ferroptosis, CTSB has been identified as a potential target for treating pancreatic cancer PMID 39988270.
• Therapeutic Complexity (Dual Role): While generally neuroprotective in the context of exercise, CTSB can be released by microglia under inflammatory conditions to activate IL-1β, potentially fueling neuroinflammation. Consequently, some researchers suggest that CTSB inhibition (rather than activation) might be beneficial in specific inflammatory brain diseases, highlighting the need for context-specific modulation PMID 40818821PMID 35283168.

1. Oncology and Enzyme-Responsive Drug Delivery

• Carbon Monoxide Delivery: A 2025 study synthesized an enzyme-triggered carbon monoxide-releasing molecule (ET-CORM) conjugated to the antibody trastuzumab. This conjugate releases therapeutic CO specifically upon cleavage by cancer-associated CTSB, offering a novel approach for some cancers PMID 41199686.
• Tumor-Targeting Linkers: The GPLG peptide sequence has been validated as an effective CTSB-cleavable linker, facilitating the design of stable and precise tumor-targeting drug conjugates PMID 40978411.
• Glioblastoma Multiforme (GBM): A CTSB-responsive brain-targeted delivery system was developed to modulate the immune microenvironment. This system promotes the polarization of tumor-associated macrophages to a pro-inflammatory phenotype, improving anti-GBM immune responses PMID 38358804.

2. Sepsis and Inflammation

• Sepsis-Induced Lung Injury: Research from 2025 indicates that CTSB exacerbates sepsis-induced lung injury by promoting pyroptosis (programmed cell death) in lung epithelial cells, suggesting CTSB as a critical therapeutic target for this condition PMID 40394663.

3. Neuroprotection and Diagnostics

• Parkinson’s Disease (PD): The use of Chitosan-coated Tanshinone-loaded nanocarriers (CS-TAN-NLCs) was shown to reduce oxidative stress, inflammatory markers, and CTSB levels, effectively enhancing brain delivery and therapeutic management of PD PMID 37598133.
• Intracerebral Hemorrhage: Transcriptomic analysis revealed that the herbal formula BYHWD exerts neuroprotective effects by enhancing autophagy through the inhibition of CTSB expression PMID 37957754.
• Pre-eclampsia: Elevated levels of CTSB have been identified as a promising biomarker for predicting the severity of pre-eclampsia in pregnant patients PMID 39475373.