Exploring the role of Cathepsin S in mitochondrial energy metabolism: implications for cancer progression and therapeutic targeting.

Abstract

Cathepsin S (CTSS) is a lysosomal cysteine protease traditionally recognized for its roles in protein degradation and immune responses, but emerging evidence highlights its critical involvement in cancer progression through the regulation of mitochondrial energy metabolism, tumor microenvironment modulation, and apoptosis. CTSS regulates mitochondrial calcium uptake by controlling the mitochondrial calcium uniporter (MCU), thus maintaining mitochondrial membrane potential and oxidative phosphorylation (OXPHOS). Inhibition of CTSS leads to mitochondrial calcium overload, increased reactive oxygen species (ROS) generation, impaired autophagy, and apoptosis, as demonstrated particularly in glioblastoma models. Additionally, CTSS promotes cancer progression by degrading extracellular matrix components, stimulating angiogenesis, and facilitating invasion and metastasis. Selective CTSS inhibitors enhance chemotherapy sensitivity and reduce tumor growth in various preclinical cancer models, including both glycolytic and OXPHOS-dependent tumors. However, most data originate from preclinical studies, limiting immediate clinical applicability. Moreover, CTSS inhibition may elevate ROS levels, posing potential harm to normal cells, and the complex tumor microenvironment presents challenges for targeted therapies. Overall, CTSS is a pivotal regulator that integrates mitochondrial function with tumor microenvironment dynamics, making it a promising therapeutic target. It represents a compelling target for future precision oncology strategies, offering dual benefits of direct tumor suppression and improved sensitivity to existing therapies. Nevertheless, further mechanistic studies and clinical validation are required to fully exploit CTSS's potential in cancer treatment, including deeper investigation into the molecular events linking CTSS inhibition to changes in autophagy, mitochondrial biogenesis, and metabolic reprogramming across diverse cancer subtypes.