Targeting fatty acid synthase suppresses tumor development in NF2/CDKN2A-deficient pleural mesothelioma

Our plain-English summary of Targeting fatty acid synthase suppresses tumor development in NF2/CDKN2A-deficient pleural mesothelioma, by S. Karnan, A. Ota, M.N. Hasan, et al (Cell Death & Disease, 2026).

The study

• Authors: S. Karnan, A. Ota, M.N. Hasan, H. Murakami, M.L. Rahman, M. Wahiduzzaman, M.T.A. Shihan, N. Jahan, L.Q. Vu, I. Hanamura, A. Inoko, M. Riku, H. Ito, Y. Kaneko, Y. Lin, T. Hyodo, H. Konishi, S. Tsuzuki, Y. Hosokawa
• Journal: Cell Death & Disease
• Published: 2026;17(1)
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pleural mesothelioma (PM) is an uncommon yet deadly cancer linked to asbestos exposure. The lack of effective early diagnosis and treatment leads to reduced life expectancy among patients with PM. This study aims to identify a novel molecular target inhibitor to develop more effective therapeutics for PM. Our drug screening assay showed that the fatty acid synthase (FASN) inhibitor cerulenin demonstrates strong and selective antiproliferative properties against NF2/CDKN2A(p16)-deficient PM cells, surpassing the effects of C75, cisplatin or pemetrexed. FASN protein is frequently detected in NF2/p16-deficient PM tumor-derived tissues (15/15, 100%), but rarely in NF2/p16-intact PM tumors (8/25, 32%). Notably, cerulenin administration successfully reduced the growth of NF2/p16-deficient PM tumors in xenografted mice. Cerulenin inhibits mitochondrial fission by targeting dynamin-related protein 1 (DRP1) in NF2/p16-deficient cells. Moreover, the disruption of the FASN gene leads to increased ubiquitination of DRP1. These findings suggest that FASN might play a role in the tumorigenesis of PM cells through the regulation of mitochondrial dynamics. This research offers a novel perspective on the potential development of precision medicine for PM.

© 2026. The Author(s).

In plain English

This laboratory study tested whether blocking fatty acid synthase (FASN) suppresses pleural mesothelioma (PM) cells lacking the NF2 and CDKN2A (p16) tumor suppressor genes; the authors describe PM as a cancer commonly linked to asbestos exposure. Screening 364 compounds on genome-edited human mesothelial cells showed the FASN inhibitor cerulenin had the most potent antiproliferative activity against NF2/p16-double knockout (DKO) cells. Average IC50 values were 5 to 7.5 micromolar in NF2/p16-DKO lines and MSTO-211H, compared with about 20 micromolar in NF2+/+p16+/+ lines; pemetrexed, cisplatin and C75 were relatively ineffective. In 45 human PM tissue samples, FASN was detected in 15/15 (100%) NF2/p16-negative cases versus 8/25 (32%) NF2/p16-positive cases. In SCID mice (n = 5 per group), intraperitoneal cerulenin reduced growth of NF2/p16-deficient MSTO-211H tumors without body-weight loss. Cerulenin and FASN knockout reduced DRP1 phosphorylation, promoted mitochondrial fusion, increased apoptosis markers, and FASN knockout increased DRP1 ubiquitination. The authors concluded cerulenin preferentially inhibits PM cells lacking NF2 and/or p16 through regulation of mitochondrial dynamics.

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: Laboratory study combining a drug-screening and cell-culture experiments in genome-edited human mesothelial and mesothelioma cell lines, immunohistochemistry on a human tissue array, public-database survival analysis, and mouse xenograft and toxicity experiments
• Who was studied: Human mesothelial cell lines (MeT-5A, HOMC-B1) and mesothelioma cell lines (ACC-MESO-4, Y-MESO-14, Y-MESO-9, NCI-H2452, MSTO-211H, NCI-H290, NCI-2052) with CRISPR-generated knockouts; 45 human PM tissue samples and 2 mesothelium samples on a commercial tissue array; TCGA PM dataset (43 high- and 43 low-FASN patients); female SCID and BALB/c mice, 5 per group; work done at Aichi Medical University, Japan
• Exposure: Pharmacological FASN inhibition (cerulenin, compared with C75, cisplatin, pemetrexed and desoxyrhaponticin) and genetic FASN knockout, in cells deficient in NF2 and CDKN2A(p16); mice received cerulenin 20 mg/kg intraperitoneally. Asbestos is named only as the background cause of pleural mesothelioma.
• Main results:
  • Cerulenin, but not C75, showed the strongest antiproliferative activity against NF2/p16-DKO cells in the 364-compound screen
  • Average IC50 for cerulenin was 5 to 7.5 micromolar in NF2/p16-DKO mesothelial lines and MSTO-211H cells, versus about 20 micromolar in NF2+/+p16+/+ lines
  • FASN was detected in all 15 NF2/p16-negative PM tissue cases and in 8 of 25 NF2/p16-positive cases
  • In TCGA PM data, patients with higher FASN expression had shorter overall survival
  • In SCID mice bearing NF2/p16-deficient MSTO-211H tumors, intraperitoneal cerulenin inhibited tumor growth compared with vehicle, with no body-weight loss
  • In BALB/c mice, cerulenin produced no histopathological changes in heart, liver or kidneys and no changes in liver or kidney function tests
  • FASN knockout (TKO) cells proliferated more slowly than DKO cells, with decreased Akt and DRP1 phosphorylation and increased cleaved PARP and caspase-3
  • DRP1 ubiquitination was higher in FASN-knockout (TKO) cells than in DKO cells, and MG-132 restored DRP1 expression
• The authors' conclusion: The authors concluded that in their genome-edited human mesothelial cell model the FASN inhibitor cerulenin preferentially has an antiproliferative effect on PM cells lacking NF2 and/or p16 through regulation of mitochondrial dynamics, and suggested potential clinical utility
• Limitations the authors state:
  • The somatic mutation status of NF2 and/or p16 in the tissues stained for FASN was not investigated
  • The antitumor effect in mice was shown with only one human PM cell line, MSTO-211H, so tests in primary human PM-derived tumors are needed

Topics

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

Medical terms in this study, explained in our Lexicon: CDKN2A, Pleural Mesothelioma, Asbestos Exposure, Life Expectancy, Cisplatin, Pemetrexed (Alimta), Carcinogenesis.

Related studies

• CAMK2D: a novel molecular target for BAP1-deficient malignant mesothelioma — S. Karnan, A. Ota, et al. (2023)
• Establishment and characterization of CRISPR/Cas9-mediated NF2-/- human mesothelial cell line: Molecular insight into fibroblast growth factor receptor 2 in malignant pleural mesothelioma — M. Wahiduzzaman, S. Karnan, et al. (2019)
• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)
• Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice — J. Badhai, G.K. Pandey, et al. (2020)
• De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma — D. Xu, Y. Gao, et al. (2025)
• Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma — G. Guo, J. Chmielecki, et al. (2015)

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