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α-ketoglutarate/succinate ratio imbalance impairs thymine DNA glycosylase function and base excision repair process increasing susceptibility to pancreatic cancer
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  • Published: 21 February 2026

α-ketoglutarate/succinate ratio imbalance impairs thymine DNA glycosylase function and base excision repair process increasing susceptibility to pancreatic cancer

  • Silvia Malatesta1,2 na1,
  • Virginia Vigiano Benedetti3 na1,
  • Emanuela Salviati4,
  • Barbara Illi5,
  • Isabella Manni6,
  • Emanuele Middonti7,8,
  • Gian Luca Rampioni Vinciguerra  ORCID: orcid.org/0000-0003-0739-16689,
  • Valerio Licursi  ORCID: orcid.org/0000-0002-8172-14375,
  • Francesca Troilo5,
  • Gianni Colotti  ORCID: orcid.org/0000-0002-9913-06355,
  • Lina Cipolla10,
  • Simone Sabbioneda10,
  • Livia Perfetto1,
  • Giulia Piaggio  ORCID: orcid.org/0000-0003-2114-18926,
  • Federico Bussolino  ORCID: orcid.org/0000-0002-5348-13417,8,
  • Federica Di Nicolantonio  ORCID: orcid.org/0000-0001-9618-20107,8,
  • Pietro Campiglia4,
  • Eduardo Maria Sommella  ORCID: orcid.org/0000-0001-8654-64314,
  • Mattia Mori11,
  • Chiara Cencioni  ORCID: orcid.org/0000-0001-6284-539X12 na2 &
  • …
  • Francesco Spallotta  ORCID: orcid.org/0000-0002-0466-62861,2 na2 

Cell Death & Disease , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cancer metabolism
  • DNA methylation
  • Pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, with chronic metabolic disorders increasing risk and severity. Prolonged exposure to altered metabolism changes specific metabolite levels, impacting epigenetic landscape contributing neoplastic lesion acquisition. This study examines the interplay between metabolism and epigenetics in dysmetabolic-driven PDAC tumorigenesis, exploiting LSL-KrasG12D;PDX-1-Cre mice (KC mice) exposed to high-fat diet (HFD) and KRAS-mutated human pancreatic ductal epithelial (HPDE) cells. Untargeted metabolomics of HFD-fed KC pancreata reveals altered free fatty acid and elevated S-adenosyl methionine levels during tumorigenesis. Targeted metabolomics shows increased succinate alongside reduced α-ketoglutarate levels. This imbalance suggests an epigenetic derangement, targeting DNA methylation. In KRAS-mutated HPDE cells exposed to altered metabolism, the DNA demethylation complex of ten-to-eleven-translocation methylcytosine 1 and thymine DNA glycosylase (TDG) is disrupted, leading to iterative cytosine modification and apurinic/apyrimidinic (AP) site accumulation. Succinate directly binds TDG at arginine 275, hyperactivating it and increasing AP site formation. This alteration combined with the methylation-prone metabolic environment, impairs the base excision repair pathway by hypermethylating and downmodulating DNA ligases LIG1 and LIG3. This predisposes to genomic instability and pancreatic preneoplastic lesion development. These findings uncover a metabolic-epigenetic axis in dysmetabolic PDAC, highlighting how metabolite-driven epigenetic changes compromise DNA repair and drive tumorigenesis.

Data availability

The RNA sequencing datasets are publicly available at NCBI’s Gene Expression Omnibus (GEO) repository, under accession number GSE302730 located at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE302730. Any additional information required to reanalyze the data reported in this work paper is available from the lead contact upon request, Dr. Francesco Spallotta (francesco.spallotta@uniroma1.it) and Dr. Chiara Cencioni (chiara.cencioni@cnr.it). This study did not generate new unique reagents.

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Funding

This research was funded by the AIRC, Associazione Italiana per la Ricerca sul Cancro (AIRC), My First AIRC “Giorgio e Adriana Squinzi” MFAG number 23099 to Francesco Spallotta, MFAG number 28858 to Livia Perfetto, Start Up number 30656 to Gian Luca Rampioni Vinciguerra and IG number 22910 to Federico Bussolino; Sapienza University of Rome, “Progetto Ateneo 2023” to Francesco Spallotta; funded by European Union-Next Generation EU, Missione 4 C2 Investimento 1.1 PRIN-PNRR number P2022R7WRC; CUP B53D23025120001 to Chiara Cencioni and Eduardo Maria Sommella; PRIN-PNRR number P2022E3BTH; CUP B53D23024970001 to Francesco Spallotta; funded by PNRR M4C2—Dalla ricerca all’impresa—3.1: Fondo per la realizzazione di un sistema integrato di infrastrutture di ricerca e innovazione “Potentiating the Italian Capacity for Structural Biology Services in Instruct-ERIC (ITACA.SB)” CUP: B53C22001790006; PNRR PE8 Age-IT., cofounding from Next Generation EU [DM 1557 11.10.2022], in the context of the National Recovery and Resilience Plan, Investment PE8—Project Age-It: “Ageing Well in an Ageing Society”; Project PRIN MIUR 2022HYF8KS to Gianni Colotti; MUR (PNRR D3 4 Health) and FPRC 5xmille Ministero Salute 2022 – CARESS and Ricerca Corrente 2025 to Federico Bussolino; Project "Pathogen Readiness Platform for CERIC ERIC upgrade" - PRP@CERIC CUP J97G22000400006 to Pietro Campiglia.

Author information

Author notes

  1. These authors contributed equally: Silvia Malatesta, Virginia Vigiano Benedetti.

  2. These authors jointly supervised this work: Chiara Cencioni, Francesco Spallotta.

Authors and Affiliations

  1. Department of Biology and Biotechnologies “Charles Darwin”, Sapienza University, Rome, Italy

    Silvia Malatesta, Livia Perfetto & Francesco Spallotta

  2. Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, Rome, Italy

    Silvia Malatesta & Francesco Spallotta

  3. Department of Translational Medicine, Catholic University of the Sacred Heart, Rome, Italy

    Virginia Vigiano Benedetti

  4. Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy

    Emanuela Salviati, Pietro Campiglia & Eduardo Maria Sommella

  5. Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

    Barbara Illi, Valerio Licursi, Francesca Troilo & Gianni Colotti

  6. SAFU Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy

    Isabella Manni & Giulia Piaggio

  7. Department of Oncology, University of Torino, Orbassano, Italy

    Emanuele Middonti, Federico Bussolino & Federica Di Nicolantonio

  8. Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy

    Emanuele Middonti, Federico Bussolino & Federica Di Nicolantonio

  9. Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sant’Andrea Hospital, Sapienza University, Rome, Italy

    Gian Luca Rampioni Vinciguerra

  10. Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza”, National Research Council (IGM-CNR), Pavia, Italy

    Lina Cipolla & Simone Sabbioneda

  11. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy

    Mattia Mori

  12. Institute of System Analysis and Informatics “Antonio Ruberti”, National Research Council (IASI-CNR), Rome, Italy

    Chiara Cencioni

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  1. Silvia Malatesta
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  2. Virginia Vigiano Benedetti
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Contributions

Each author significantly contributed to the conceptualization of the study, the acquisition, analysis, or interpretation of data, as well as the drafting of the paper. All authors approved the final version of the manuscript. CC and FS designed the research and carried out experiments; SM, VVB, ES, BI, IM, and EM performed the experiments; VL, LP, EMS analyzed data and performed bioinformatics; GLRV performed histological evaluation; EMS supervised metabolomics analyses; MM performed molecular dynamics; LC and SS performed PLA experiments; FT and GC performed SPR experiments; GP, FB, FDN, PC gave conceptual advice; CC and FS wrote the manuscript and supervised the study. All authors discussed the results and implications of the study.

Corresponding authors

Correspondence to Chiara Cencioni or Francesco Spallotta.

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Competing interests

The authors declare no competing interests.

Ethics approval

All methods were performed in accordance with the relevant guidelines and regulations. All animal studies were approved by the Institutional Animal Care of Regina Elena National Cancer Institute (Rome, Italy) and by the Government Committee of National Minister of Health (protocol permit number: 362/2021-PR) and conducted according to EU Directive 2010/63/EU and Italian D.L. 2614/2014 for animal experiments following the Institutional Guidelines for Animal Care and Welfare. The present study does not include human subjects.

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Malatesta, S., Vigiano Benedetti, V., Salviati, E. et al. α-ketoglutarate/succinate ratio imbalance impairs thymine DNA glycosylase function and base excision repair process increasing susceptibility to pancreatic cancer. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08475-w

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  • Received: 04 September 2025

  • Revised: 27 January 2026

  • Accepted: 09 February 2026

  • Published: 21 February 2026

  • DOI: https://doi.org/10.1038/s41419-026-08475-w

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