{
  "abstract": "Background/Objectives: Cathepsins, a family of lysosomal proteases essential for cellular proteostasis, have functions that extend beyond canonical degradation and recycling processes. Their dysregulation has been strongly associated with tumorigenesis, where cathepsins promote multiple hallmarks of cancer, including extracellular matrix remodeling, invasion, proliferation, and inflammation. Both intracellular and extracellular cathepsin activities contribute to tumor microenvironment shaping and influence the response to anticancer therapies, particularly chemoresistance. This review aims to summarize current knowledge on the biochemical regulation of cathepsins in cancer and evaluate their potential as therapeutic targets. Methods: A comprehensive literature analysis was conducted, focusing on recent in vitro, in vivo, and translational studies examining cathepsins’ functions, substrate specificity, biochemical pathways, and pharmacological modulations. Special attention was given to research addressing inhibitor development, therapeutic targeting strategies, and challenges associated with selectivity, delivery, and model variability. Results: Evidence indicates that cathepsins exhibit a multifaceted role in cancer. Extracellular cathepsins facilitate matrix degradation and metastatic dissemination, while intracellular cathepsins regulate key signaling networks that promote tumor cell survival, proliferation, autophagy, and inflammatory responses. Furthermore, cathepsins contribute to tumor microenvironment remodelling and modulate sensitivity to chemotherapy, supporting multiple mechanisms of therapy resistance. Although preclinical studies highlight promising therapeutic opportunities, significant limitations persist, including poor inhibitor specificity, challenges in drug delivery, compensatory activation among cathepsin isoforms that may sustain overlapping proteolytic functions, and heterogeneous responses across tumor types. Conclusions: Targeting cathepsins is an emerging strategy in oncology, but effective translation requires a deeper understanding of the complex biochemical networks they regulate. Given their broad and interconnected roles, clarifying these pathways is essential to anticipate global effects and potential toxicities. Future work should therefore define this molecular hub and develop approaches that ensure selective and safe cathepsin modulation.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy",
    "Medicum, Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, P.O. Box 63, FIN-00014 Helsinki, Finland",
    "Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, FIN-00290 Helsinki, Finland",
    "Department of Medicine, Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Mariapia Vietri",
      "orcid": "0009-0001-6471-5246"
    },
    {
      "affs": [
        0
      ],
      "name": "Alessia Delizia"
    },
    {
      "affs": [
        0
      ],
      "name": "Tania Ciaglia",
      "orcid": "0000-0002-6592-4373"
    },
    {
      "affs": [
        0
      ],
      "name": "Carla Sardo",
      "orcid": "0000-0002-7819-9449"
    },
    {
      "affs": [
        0
      ],
      "name": "Simona Musella",
      "orcid": "0000-0001-8312-4241"
    },
    {
      "affs": [
        0
      ],
      "name": "Veronica Di Sarno",
      "orcid": "0000-0002-1397-5240"
    },
    {
      "affs": [
        0
      ],
      "name": "Carmine Ostacolo",
      "orcid": "0000-0003-3715-8680"
    },
    {
      "affs": [
        0
      ],
      "name": "Ornella Moltedo",
      "orcid": "0000-0002-0526-2152"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Dan Lindholm"
    },
    {
      "affs": [
        0
      ],
      "name": "Mario Felice Tecce",
      "orcid": "0000-0003-2355-6047"
    },
    {
      "affs": [
        0
      ],
      "name": "Pietro Campiglia",
      "orcid": "0000-0002-1069-2181"
    },
    {
      "affs": [
        0
      ],
      "name": "Alessia Bertamino"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Maria Rosaria Miranda",
      "orcid": "0009-0005-8296-1888"
    },
    {
      "affs": [
        0
      ],
      "name": "Vincenzo Vestuto",
      "orcid": "0000-0002-3603-5526"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ft2929jkgkj28.bib",
  "cited_by": 0,
  "doi": "10.3390/biom16111629",
  "fulltext_url": null,
  "id": "ft2929jkgkj28",
  "issns": [
    "2218-273X"
  ],
  "landing_url": "https://www.mdpi.com/2218-273X/16/11/1629",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-08",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/ft2929jkgkj28.ris",
  "sources": [
    {
      "first_seen": "2026-11-10T00:21:28Z",
      "native_id": "10.3390/biom16111629",
      "source": "crossref",
      "url": "https://www.mdpi.com/2218-273X/16/11/1629"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "issn:2218-273X",
      "subfield": "general"
    }
  ],
  "title": "Biochemical Basis and Therapeutic Relevance of Cathepsins in Cancer: Recent Advances",
  "title_text": "Biochemical Basis and Therapeutic Relevance of Cathepsins in Cancer: Recent Advances",
  "type": "peer-reviewed",
  "updated_at": "2026-11-10T00:21:28Z",
  "url": "https://research.draconitic.com/paper/ft2929jkgkj28",
  "venue": "Biomolecules",
  "versions": []
}