Research progress on the regulation of mesothelioma driven by deubiquitinating enzyme BAP1

Our plain-English summary of Research progress on the regulation of mesothelioma driven by deubiquitinating enzyme BAP1, by W.T. Xuan, Y. Dong, S.Y. Ma, et al (Clinical and Experimental Medicine, 2026).

The study

• Authors: W.T. Xuan, Y. Dong, S.Y. Ma, M. Liu, X.Q. Liu, N.N. Yao, L.X. Hu, L.L. Shi, L. Ma, J.H. Bai, B. Huang
• Journal: Clinical and Experimental Medicine
• Published: 2026;26(1)
• Type of article: Review
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is a highly aggressive malignancy that develops through the combined influence of several factors, including environmental exposure, genetic susceptibility, immune status, and aberrant activation or dysregulation of signaling pathways. The BAP1 gene, a tumor suppressor located at chromosome 3p21.1, plays a pivotal role in maintaining genomic stability by functioning as a deubiquitinating enzyme in critical processes such as DNA damage repair, cell cycle regulation, and chromatin remodeling. Its proper activity requires nuclear localization via the nuclear localization signal (NLS) domain. When BAP1 undergoes a truncation mutation, the NLS loses its function and the protein is retained in the cytoplasm; whereas missense mutations in the UCH domain, whilst not necessarily altering subcellular localisation, can directly lead to the loss of deubiquitinase activity, thereby promoting tumour development.Consequently, elucidating the signaling pathways governed by BAP1, designing targeted therapeutic strategies for BAP1-mutant cancers, and implementing preventive interventions in BAP1 mutation carriers represent urgent clinical and research priorities.

© 2026. The Author(s).

In plain English

This article is a review: the authors summarized published research on the tumor suppressor gene BAP1 and its role in mesothelioma, without describing how they searched the literature. In the background, they cited sources stating that asbestos exposure accounts for over 80% of pleural and 10–15% of peritoneal mesothelioma cases. The studies the review described included a sequencing study of 128 untreated diffuse pleural mesotheliomas that found BAP1 alterations in 62 (48%). They also included experimental work reporting that BAP1 inactivation lowered the threshold of asbestos exposure needed for malignant transformation, and a mouse study in which 22 of 26 animals with BAP1, CDKN2A and NF2 all deleted developed mesothelioma. The review also covered loss of BAP1 staining as a diagnostic marker and early drug trials, including a tazemetostat trial in patients with BAP1-inactivated pleural mesothelioma that reported a 54% disease control rate after 12 weeks. The authors concluded that understanding BAP1 pathways, developing targeted treatments for BAP1-mutant cancers and preventive measures for BAP1 mutation carriers are urgent priorities.

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 research. No literature search method is described, and no new data were collected.
• Who was studied: Published literature (72 references) on BAP1 structure and function, its mechanisms in mesothelioma, and its use in diagnosis and treatment. The cited studies include human tumor series, cell experiments, mouse models and early clinical trials.
• Exposure: The review's focus is BAP1 gene alterations, not a specific exposure. Asbestos appears in the background, citing other sources that it accounts for over 80% of pleural and 10–15% of peritoneal cases. It also appears in cited experimental work on BAP1 loss and asbestos-induced carcinogenesis. No fiber types are specified.
• Main results:
  • A cited retrospective sequencing study of 128 samples from untreated patients with diffuse pleural mesothelioma found that BAP1 alterations were the most common genomic variant: 62 samples, 48%.
  • The review reported that experimental studies, in human mesothelial cells with reduced BAP1 and in animals with BAP1 haploinsufficiency, showed that BAP1 inactivation lowers the threshold of asbestos exposure required for malignant transformation. HMGB1 was described as part of the proposed mechanism.
  • In a cited conditional knockout mouse study, approximately 20% of mice with BAP1 loss combined with NF2 or CDKN2A deletion developed mesothelioma.
  • In the same cited mouse study, 85% (22 of 26) of mice with all three of BAP1, CDKN2A and NF2 deleted developed mesothelioma.
  • The review stated that mesothelioma patients carrying germline (inherited) BAP1 mutations have improved survival. It linked this to reduced HIF-1α activity.
  • A cited retrospective review of 56 reactive mesothelial hyperplasia cases and 64 mesothelioma cases found that 45.3% of the mesotheliomas were BAP1-negative.
  • In that same cited review, 19.6% of the reactive mesothelial hyperplasia cases showed loss of nuclear BAP1.
  • A cited clinical trial of tazemetostat (Zauderer et al.) enrolled patients with pleural mesothelioma harboring BAP1 inactivation. In these patients, the disease control rate after 12 weeks of treatment was reported as 54%.
  • In a cited trial of oral rucaparib (Fennell et al.) in 26 eligible patients with BAP1- or BRCA1-deficient mesothelioma, over half of the patients achieved disease control at 12 weeks.
• The authors' conclusion: The authors concluded that clarifying the signaling pathways governed by BAP1, designing targeted therapies for BAP1-mutant cancers, and preventive interventions in BAP1 mutation carriers are urgent clinical and research priorities.
• Limitations the authors state:
  • The authors noted that one cited study on combined BAP1 and KRAS/TP53 mutations (Marazioti) used only mouse cell models. They said it does not match the typical mutation pattern in human pleural mesothelioma patients.
  • The authors stated that the pathways linking TERT promoter mutations to mesothelioma have not been clearly identified, so they left them out of their mechanism diagram.

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, BAP1, Environmental Exposure.

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