Damage-Associated Molecular Patterns in Mesothelioma: Drivers of Inflammation and Therapeutic Targets

Our plain-English summary of Damage-Associated Molecular Patterns in Mesothelioma: Drivers of Inflammation and Therapeutic Targets, by A. Molinario, F. Caprioglio, A.A. Rilievo, et al (International Journal of Molecular Sciences, 2026).

The study

• Authors: A. Molinario, F. Caprioglio, A.A. Rilievo, M.E. Bianchi, R. Mezzapelle
• Journal: International Journal of Molecular Sciences
• Published: 2026;27(17)
• Type of article: Review
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is a rare and aggressive malignancy arising from mesothelial cells. Despite recent advances in systemic therapies, overall survival remains limited, underscoring the need for a deeper mechanistic understanding of disease pathogenesis and novel therapeutic strategies. In mesothelioma, chronic tissue injury induced by asbestos fibers leads to sustained activation of innate immune pathways and chronic inflammation that actively promote tumorigenesis. The release of Damage-Associated Molecular Patterns (DAMPs)-endogenous molecules that signal cellular stress and damage-contributes to establishing a self-sustaining inflammatory circuit within the pleural microenvironment that promotes tumor initiation and progression and immune evasion. Among DAMPs, High-Mobility Group Box 1 (HMGB1) has emerged as a key regulator of mesothelioma pathogenesis. Several studies demonstrated that mesothelial cells actively secrete HMGB1 in response to asbestos exposure, driving macrophage recruitment, cytokine production, and chronic inflammation. Beyond HMGB1, additional DAMPs-including IL-33, extracellular ATP, cell-free nucleic acids, heat shock proteins, and calreticulin-contribute to inflammasome activation, stromal remodeling, and immune dysregulation. Recent evidence suggests that DAMP signaling in mesothelioma is dysregulated, resulting in chronic inflammation coupled with ineffective antitumor immunity. This review provides a comprehensive synthesis of DAMP biology in mesothelioma, highlighting the emerging therapeutic opportunities targeting DAMP-associated pathways.

In plain English

This article was a review. The authors summarized published research on damage-associated molecular patterns (DAMPs) in mesothelioma. DAMPs are the body's own molecules that stressed, injured or dying cells release or expose on their surface, signaling damage to the immune system. The authors did not collect or analyze new data. Drawing on the studies they reviewed, they described chronic asbestos exposure as causing persistent cell damage and death, continuous DAMP release, and ongoing inflammation. The DAMP they discussed most was a protein called HMGB1. Serum HMGB1 was elevated in asbestos-exposed people and mesothelioma patients, but is also raised in many other conditions, limiting its specificity for this disease. No DAMP has been validated as a predictor of progression from asbestos-related tissue injury to mesothelioma, or as a predictor of response to immune checkpoint drugs. Treatments aimed at HMGB1 remained at the preclinical stage. The authors concluded that the context-dependent effects of DAMPs are the major challenge for clinical use. They noted that most studies have examined single biomarkers.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published literature; no new data
• Who was studied: No study population of its own; the authors reviewed published laboratory, animal and clinical research on DAMPs in mesothelioma
• Exposure: Asbestos exposure in general, described as causing persistent cell damage and DAMP release; the review does not compare fiber types
• Main results:
  • Based on the reviewed literature, DAMPs are the body's own molecules that are released or exposed when cells are stressed, injured or die
  • Based on the reviewed literature, serum HMGB1 levels are elevated in asbestos-exposed subjects and in mesothelioma patients
  • Circulating HMGB1 has limited disease specificity because it is also elevated in other conditions
  • No DAMP is a validated predictor or indicator of progression from asbestos-related tissue injury to mesothelioma
  • The relevance of DAMPs to immune checkpoint inhibitor response remains largely unexplored in mesothelioma, and no DAMP has been validated as a predictive biomarker
  • HMGB1-targeting therapeutic approaches remain at the preclinical stage
• The authors' conclusion: The authors concluded that DAMPs, particularly HMGB1, connect asbestos-induced injury with innate immune activation, and that the context-dependent functions of DAMPs are the major challenge for clinical translation
• Limitations the authors state:
  • The authors noted that most studies in the field have focused on single biomarkers
  • The authors noted that direct clinical evidence for circulating mitochondrial DNA as a diagnostic or prognostic biomarker in mesothelioma is limited
  • The authors noted that it is not yet established whether the BAP1–HDAC1–HMGB1 axis matters in sporadic (non-inherited) mesothelioma

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Inflammation, Mesothelial Cells, Overall Survival, Chronic Inflammation, Carcinogenesis, High Mobility Group Box 1 (HMGB1), Asbestos Exposure.

Related studies

• Gene expression of mesothelioma in vinylidene chloride-exposed F344/N rats reveal immune dysfunction, tissue damage, and inflammation pathways — P.E. Blackshear, A.R. Pandiri, et al. (2015)
• Interleukin-6 as a therapeutic target in candidate inflammatory diseases — N. Nishimoto (2010)
• Crosstalk between DNA Damage and Inflammation in the Multiple Steps of Carcinogenesis — S. Kawanishi, S. Ohnishi, et al. (2017)
• Role of nitrative and oxidative DNA damage in inflammation-related carcinogenesis — M. Murata, R. Thanan, et al. (2012)
• Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation — H. Yang, Z. Rivera, et al. (2010)
• Asbestos-induced cellular and molecular alteration of immunocompetent cells and their relationship with chronic inflammation and carcinogenesis — H. Matsuzaki, M. Maeda, et al. (2012)

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