ACTREC, Tata Memorial Centre · Mumbaiindraneel.mittra@gmail.com
Translational Research Laboratory
ACTRECTata Memorial
CentreNavi Mumbai
Cell-Free Chromatin: Rethinking the Foundations of Biology

Publications

Our Publications

Themes

  1. 1. Cell-free chromatin particles as drivers of evolutionary change
  2. 2. Cell-free chromatin particles as pathological entities
  3. 3. Therapeutic Strategies: Neutralisation of Cell-free Chromatin

“Cited by” counts: OpenAlex, October 2026. Who cites our work →

1. Cell-free chromatin particles as drivers of evolutionary change

Together, these four papers propose that circulating cell-free chromatin particles (cfChPs) released during cell death are biologically active mobile genetic elements, not inert debris. They demonstrate that cfChPs can enter recipient cells, function as autonomous “satellite genomes,” mediate horizontal transfer of genetic information across cellular, species, and kingdom boundaries, mobilize transposable elements, and reveal evolutionary information encoded within non-coding DNA, with potential implications for genomic instability, disease, ageing, and mammalian evolution.

  1. 1. Banerjee, S., Shende, S. S., Kata, L., Lopes, R. S., Praveen, S., Joshi, R., ... & Mittra, I. (2025). Horizontally transferred cell-free chromatin particles function as autonomous ‘satellite genomes’ and vehicles for transposable elements within host cells. Elife, 13, RP103771. https://elifesciences.org/articles/103771 Cited by 2 (OpenAlex, opens in a new tab)

    Video Links

    https://drive.google.com/file/d/1SWc1q_3zuhT1c8-Cpe7o72uzCSnekc7W/view?usp=sharing (opens in a new tab)

    https://drive.google.com/file/d/1uN43gaSKlsk-LKd-5z_8hBqxA-Y-z8Ol/view?usp=sharing (opens in a new tab)

  2. 2. Mittra, I. (2015). Circulating nucleic acids: a new class of physiological mobile genetic elements. F1000Research, 4, 924. https://f1000research.com/articles/4-924/v1 Cited by 17 (OpenAlex, opens in a new tab)
  3. 3. Raghuram, G. V., Gupta, D., Subramaniam, S., Gaikwad, A., Khare, N. K., Nobre, M., ... & Mittra, I. (2017). Physical shearing imparts biological activity to DNA and ability to transmit itself horizontally across species and kingdom boundaries. BMC Molecular Biology, 18(1), 21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550992/ Cited by 20 (OpenAlex, opens in a new tab)
  4. 4. Joshi, R., Roy, A., Lopes, R., Kata, L., Selukar, R., Markam, M., ... & Mittra, I. (2025). Apoptosis uncovers human evolutionary heritage sequestered in non-coding DNA. bioRxiv, 2025-11. https://www.biorxiv.org/content/10.1101/2025.11.13.688179v2

2. Cell-free chromatin particles as pathological entities

DNA damage and Inflammation

These studies show that cfChPs can integrate into healthy cell genomes, inducing DNA double-strand breaks, genomic instability, and inflammation. The findings link inflammatory signalling directly to genomic injury and suggest that chronic cfChP exposure contributes to aging, somatic mosaicism, cancer, and other diseases. Together, they support a unified model of cfChP-driven disease progression.

  1. 1. Mittra, I., Nair, N. K., & Mishra, P. K. (2012). Nucleic acids in circulation: are they harmful to the host?. Journal of biosciences, 37(2), 301-312. https://www.ncbi.nlm.nih.gov/pubmed/22581336 Cited by 74 (OpenAlex, opens in a new tab)
  2. 2. Mittra, I., Khare, N. K., Raghuram, G. V., Chaubal, R., Khambatti, F., Gupta, D., ... & Dutt, A. (2015). Circulating nucleic acids damage DNA of healthy cells by integrating into their genomes. Journal of biosciences, 40(1), 91-111. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779614/ Cited by 109 (OpenAlex, opens in a new tab)
  3. 3. Mittra, I., Samant, U., Sharma, S., Raghuram, G. V., Saha, T., Tidke, P., ... & Dutt, A. (2017). Cell-free chromatin from dying cancer cells integrate into genomes of bystander healthy cells to induce DNA damage and inflammation. Cell Death Discovery, 3(1), 1-14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447133/ Cited by 70 (OpenAlex, opens in a new tab)
  4. 4. Basak, R., Nair, N. K., & Mittra, I. (2016). Evidence for cell-free nucleic acids as continuously arising endogenous DNA mutagens. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 793, 15-21. https://www.ncbi.nlm.nih.gov/pubmed/27768916 Cited by 23 (OpenAlex, opens in a new tab)
  5. 5. Mehrotra, S., & Mittra, I. (2020). Origin of genome instability and determinants of mutational landscape in cancer cells. Genes, 11(9), 1101. https://www.mdpi.com/2073-4425/11/9/1101
  6. 6. Chaudhary, S., Raghuram, G. V., & Mittra, I. (2018). Is inflammation a direct response to dsDNA breaks?. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 808, 48-52. https://www.ncbi.nlm.nih.gov/pubmed/29518635 Cited by 11 (OpenAlex, opens in a new tab)
  7. 7. Mittra, I., Pal, K., Pancholi, N., Tidke, P., Siddiqui, S., Rane, B., ... & Raghuram, G. V. (2020). Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice. PLoS One, 15(3), e0229017. https://journals.plos.org/plosone/article/authors?id=10.1371/journal.pone.0229017 Cited by 21 (OpenAlex, opens in a new tab)
  8. 8. Mittra, I., de Souza, R., Bhadade, R., Madke, T., Shankpal, P. D., Joshi, M., ... & Badwe, R. (2020). Resveratrol and Copper for treatment of severe COVID-19: an observational study (RESCU 002). MedRxiv, 2020-07. https://www.medrxiv.org/content/10.1101/2020.07.21.20151423v1
  9. 9. Shabrish, S., & Mittra, I. (2021). Cytokine storm as a cellular response to dsDNA breaks: a new proposal. Frontiers in immunology, 12, 622738. http://journal.frontiersin.org/article/10.3389/fimmu.2021.622738/full? Cited by 14 (OpenAlex, opens in a new tab)
  10. 10. Chaudhary, S., & Mittra, I. (2019). Cell-free chromatin: A newly described mediator of systemic inflammation. Journal of biosciences, 44(2), 32. https://link.springer.com/article/10.1007%2Fs12038-019-9849-7
  11. 11. V. Raghuram, G., Chaudhary, S., Johari, S., & Mittra, I. (2019). Illegitimate and repeated genomic integration of cell-free chromatin in the aetiology of somatic mosaicism, ageing, chronic diseases and cancer. Genes, 10(6), 407. https://www.mdpi.com/2073-4425/10/6/407
  12. 12. Shabrish, S., Patade,S., Shinde, S., Yelukar, R., Raghuram, GV., Lopes, R., Khare, NK., Mittra, I. (2026). Circulating Cell-Free Chromatin Particles Trigger a Unique Biphasic STING Signaling Program that Drives DNA Damage and Inflammation. bioRxiv 2026.07.28.741182; https://doi.org/10.64898/2026.07.28.741182

Aging and neurodegeneration

These studies identify cfChPs as endogenous drivers of biological aging by inducing DNA double-strand breaks, particularly at telomeres, thereby promoting senescence and genomic instability. Interventions such as the resveratrol-copper (R-Cu) combination suppressed hallmarks of aging and neurodegeneration in experimental models, highlighting cfChP neutralization as a potential anti-aging strategy.

  1. 1. Tripathy, B. K., Pal, K., Shabrish, S., & Mittra, I. (2021). A new perspective on the origin of DNA double-strand breaks and its implications for ageing. Genes, 12(2), 163. https://www.mdpi.com/2073-4425/12/2/163/htm
  2. 2. Birwatkar, S., Ghosh, T., Selukar, R., Lopes, R., Khare, N. K., Raghuram, G. V., ... & Mittra, I. (2025). DsDNA breaks inflicted by cell-free chromatin particles selectively target telomeres. Scientific Reports, 15(1), 36470. https://www.nature.com/articles/s41598-025-21509-1
  3. 3. Pal, K., Raghuram, G. V., Dsouza, J., Shinde, S., Jadhav, V., Shaikh, A., ... & Mittra, I. (2022). A pro-oxidant combination of resveratrol and copper down-regulates multiple biological hallmarks of ageing and neurodegeneration in mice. Scientific Reports, 12(1), 17209. https://www.nature.com/articles/s41598-022-21388-w Cited by 27 (OpenAlex, opens in a new tab)

Mitochondrial Damage and Oxidative Stress

These studies show that cfChPs damage both mitochondria and the genomic DNA. Following cellular uptake, cfChPs disrupt mitochondrial integrity, increasing reactive oxygen species and oxidative stress. However, cfChP-induced DNA damage can also occur independently of ROS, indicating multiple pathogenic mechanisms. This dual toxicity may contribute to inflammation, aging, neurodegeneration, and chronic disease progression.

  1. 1. Raghuram, G. V., Tripathy, B. K., Avadhani, K., Shabrish, S., Khare, N. K., Lopes, R., ... & Mittra, I. (2024). Cell-free chromatin particles released from dying cells inflict mitochondrial damage and ROS production in living cells. Cell death discovery, 10(1), 30. https://rdcu.be/dv20s Cited by 18 (OpenAlex, opens in a new tab)
  2. 2. Jain, K., Raghuram, G. V., Lopes, R., Khare, N. K., Shabrish, S., & Mittra, I. (2024). Cell-free chromatin particles damage genomic DNA of healthy cells via an ROS-independent mechanism. BioRxiv, 2024-08. https://www.biorxiv.org/content/10.1101/2024.08.16.608226v1

Cellular Reprogramming

These publications suggests that cell-free chromatin particles (cfChPs) can alter cellular identity and induce stem-like properties. These studies They show that chromatin-associated factors can reprogram differentiated cells into cancer stem-like states, while recent advances indicate the potential generation of pluripotent stem cells using cfChPs. These findings imply that horizontally transferred chromatin information may influence regeneration, disease progression, and tumor initiation by promoting cellular plasticity and stemness.

  1. 1. Mittra, I., Shabrish, S. (2026). A method, a kit and the use of pluripotent stem cells induced using cell-free chromatin particle (cfChPs). (WIPO Patent Publication No. WO/2026/078725). World Intellectual Property Organization. https://patentscope.wipo.int/search/en/WO2026078725
  2. 2. Shabrish, S., Naorem, L. D., Mohanty, S., Kumar, R., Lopes, R., Akhter, N., ... & Mittra, I. (2025). Induction of cancer stem cells from mouse fibroblasts. Scientific Reports, 15(1), 25489. https://www.nature.com/articles/s41598-025-09686-5 Cited by 1 (OpenAlex, opens in a new tab)

Cancer Metastasis

These studies propose that metastases may arise de novo within distant organs through cfChP-mediated transformation of target cells, rather than solely by cancer cell migration. Histological differences between primary and metastatic tumors support this model. If validated, this paradigm could redefine cancer dissemination and identify cfChP blockade as a strategy to prevent metastasis.

  1. 1. Singh, A., Jambhekar, N., Shet, T., Ramadwar, M., Dikshit, R., & Mittra, I. (2025). Are metastatic tumors histologically similar to the primary? Result of a retrospective blinded experiment. International Journal of Surgery Open, 63(2), 176-177. https://journals.lww.com/ijsopen/fulltext/2025/04000/are_metastatic_tumors_histologically_similar_to.21.aspx
  2. 2. Raghuram, G. V., Pal, K., Shende, S., Khare, N. K., Jadhav, V., Shinde, S., ... & Mittra, I. (2023). Evidence that metastases arise de novo as new cancers from cells of target organs. bioRxiv, 2023-08. https://www.biorxiv.org/content/10.1101/2023.08.09.552586v3
  3. 3. Raghuram, G. V., Pal, K., Sriram, G., Khan, A., Joshi, R., Jadhav, V., ... & Mittra, I. (2024). Therapeutic interventions on human breast cancer xenografts promote systemic dissemination of oncogenes. Plos one, 19(2), e0298042. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0298042 Cited by 5 (OpenAlex, opens in a new tab)

Immune check-points

Together, the published study and the accompanying manuscript identify circulating cell-free chromatin particles (cfChPs) released from dying cells as potent endogenous immune activators. The earlier study showed that cfChPs activate immune checkpoints in human lymphocytes, contributing to immune suppression in cancer. The current manuscript extends these findings by demonstrating that cfChPs trigger a previously unrecognized biphasic STING signalling programme that precedes DNA damage and drives inflammatory responses, establishing cfChPs as mechanistic links between cell death, DNA damage, sterile inflammation, and immune dysregulation.

  1. 1. Shabrish, S., Pal, K., Khare, N. K., Satsangi, D., Pilankar, A., Jadhav, V., ... & Mittra, I. (2024). Cell-free chromatin particles released from dying cancer cells activate immune checkpoints in human lymphocytes: implications for cancer therapy. Frontiers in immunology, 14, 1331491. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1331491/full Cited by 6 (OpenAlex, opens in a new tab)
  2. 2. Snehal Shabrish1,2*, Swamini Patade1,2, Roohi Yelukar1,2, Gorantla V. Raghuram1,2, Relestina Lopes1,2, Sushma Shinde1,2, Naveen Kumar Khare1,2, Indraneel Mittra1,2. Circulating Cell-Free Chromatin Particles Trigger a Unique Biphasic STING Signaling Program that Drives DNA Damage and Inflammation. https://doi.org/10.64898/2026.07.28.741182

3. Therapeutic Strategies: Neutralisation of Cell-free Chromatin

These studies establish the scientific rationale and translational potential of the pro-oxidant combination of resveratrol and copper (R–Cu). They demonstrate that R–Cu generates reactive oxygen species that selectively deactivate extracellular cell-free chromatin particles (cfChPs), thereby preventing their pathogenic effects. Across experimental models, R–Cu reduced chemotherapy toxicity, radiation-induced bystander effects, endotoxin sepsis, ageing and neurodegeneration, and systemic dissemination of oncogenic material. Clinical studies and exploratory trials in COVID-19, oral cancer, gastric cancer, multiple myeloma, and glioblastoma showed reduced treatment-related toxicities and attenuation of malignant hallmarks, supporting cfChP deactivation as a novel therapeutic strategy.

  1. 1. Subramaniam, S., Vohra, I., Iyer, A., Nair, N. K., & Mittra, I. (2016). A paradoxical relationship between resveratrol and copper (II) with respect to degradation of DNA and RNA. F1000Research, 4, 1145. https://f1000research.com/articles/4-1145/v2
  2. 2. Mittra, I. (2024). Exploiting the damaging effects of ROS for therapeutic use by deactivating cell-free chromatin: the alchemy of resveratrol and copper. Frontiers in pharmacology, 15, 1345786. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1345786/full Cited by 8 (OpenAlex, opens in a new tab)
  3. 3. Khanvilkar, S., & Mittra, I. (2025). Copper imparts a new therapeutic property to resveratrol by generating ROS to deactivate cell-free chromatin. Pharmaceuticals, 18(1), 132. https://pubmed.ncbi.nlm.nih.gov/39861193/ Cited by 11 (OpenAlex, opens in a new tab)
  4. 4. Mittra, I., Pal, K., Pancholi, N., Tidke, P., Siddiqui, S., Rane, B., ... & Raghuram, G. V. (2020). Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice. PLoS One, 15(3), e0229017. https://journals.plos.org/plosone/article/authors?id=10.1371/journal.pone.0229017 Cited by 21 (OpenAlex, opens in a new tab)
  5. 5. Mittra, I., de Souza, R., Bhadade, R., Madke, T., Shankpal, P. D., Joshi, M., ... & Badwe, R. (2020). Resveratrol and Copper for treatment of severe COVID-19: an observational study (RESCU 002). MedRxiv, 2020-07. https://www.medrxiv.org/content/10.1101/2020.07.21.20151423v1
  6. 6. Mittra, I., Pal, K., Pancholi, N., Shaikh, A., Rane, B., Tidke, P., ... & Nair, N. K. (2017). Prevention of chemotherapy toxicity by agents that neutralize or degrade cell-free chromatin. Annals of Oncology, 28(9), 2119-2127. https://www.ncbi.nlm.nih.gov/pubmed/28911066 Cited by 44 (OpenAlex, opens in a new tab)
  7. 7. Kirolikar, S., Prasannan, P., Raghuram, G. V., Pancholi, N., Saha, T., Tidke, P., ... & Mittra, I. (2018). Prevention of radiation-induced bystander effects by agents that inactivate cell-free chromatin released from irradiated dying cells. Cell death & disease, 9(12), 1142. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238009/ Cited by 49 (OpenAlex, opens in a new tab)
  8. 8. Agarwal, A., Khandelwal, A., Pal, K., Khare, N. K., Jadhav, V., Gurjar, M., ... & Mittra, I. (2022). A novel pro-oxidant combination of resveratrol and copper reduces transplant related toxicities in patients receiving high dose melphalan for multiple myeloma (RESCU 001). PLoS One, 17(2), e0262212. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0262212 Cited by 24 (OpenAlex, opens in a new tab)
  9. 9. Ostwal, V., Ramaswamy, A., Bhargava, P., Srinivas, S., Mandavkar, S., Chaugule, D., ... & Mittra, I. (2022). A pro-oxidant combination of resveratrol and copper reduces chemotherapy-related non-haematological toxicities in advanced gastric cancer: results of a prospective open label phase II single-arm study (RESCU III study). Medical Oncology, 40(1), 17. https://rdcu.be/cZyge Cited by 31 (OpenAlex, opens in a new tab)
  10. 10. Juthani, R., Punatar, S., & Mittra, I. (2024). New light on chemotherapy toxicity and its prevention. BJC reports, 2(1), 41. https://www.nature.com/articles/s44276-024-00064-8
  11. 11. Pilankar, A., Singhavi, H., Raghuram, G. V., Siddiqui, S., Khare, N. K., Jadhav, V., ... & Mittra, I. (2022). A pro-oxidant combination of resveratrol and copper down-regulates hallmarks of cancer and immune checkpoints in patients with advanced oral cancer: Results of an exploratory study (RESCU 004). Frontiers in oncology, 12, 1000957. https://www.frontiersin.org/articles/10.3389/fonc.2022.1000957/full
  12. 12. Bandiwadekar, C., Naorem, L. D., Moiyadi, A. V., Singh, V., Shetty, P., Epari, S., ... & Mittra, I. (2025). Attenuation of malignant phenotype of glioblastoma following a short course of the pro-oxidant combination of Resveratrol and Copper. BJC reports, 3(1), 68. https://www.nature.com/articles/s44276-025-00177-8 Cited by 2 (OpenAlex, opens in a new tab)
  13. 13. Raghuram, G. V., Pal, K., Sriram, G., Khan, A., Joshi, R., Jadhav, V., ... & Mittra, I. (2024). Therapeutic interventions on human breast cancer xenografts promote systemic dissemination of oncogenes. Plos one, 19(2), e0298042. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0298042 Cited by 5 (OpenAlex, opens in a new tab)

The studies cited below represent another nanotechnology-based approach to deactivating cfChPs: pullulan nanoparticles conjugated with anti-histone antibodies selectively recognize and remove cfChPs, providing proof of principle for targeted chromatin clearance. Complementing degradation strategies such as R-Cu, these publications expand therapeutic options and strengthen the case for cfChPs as clinically relevant pathological targets.

  1. 14. Rekha, M. R., Pal, K., Bala, P., Shetty, M., Mittra, I., Bhuvaneshwar, G. S., & Sharma, C. P. (2013). Pullulan-histone antibody nanoconjugates for the removal of chromatin fragments from systemic circulation. Biomaterials, 34(27), 6328-6338. https://www.ncbi.nlm.nih.gov/pubmed/23746856
  2. 15. Mittra, I., Pal, K., Pancholi, N., Shaikh, A., Rane, B., Tidke, P., ... & Nair, N. K. (2017). Prevention of chemotherapy toxicity by agents that neutralize or degrade cell-free chromatin. Annals of Oncology, 28(9), 2119-2127. https://www.ncbi.nlm.nih.gov/pubmed/28911066 Cited by 44 (OpenAlex, opens in a new tab)
  3. 16. Kirolikar, S., Prasannan, P., Raghuram, G. V., Pancholi, N., Saha, T., Tidke, P., ... & Mittra, I. (2018). Prevention of radiation-induced bystander effects by agents that inactivate cell-free chromatin released from irradiated dying cells. Cell death & disease, 9(12), 1142. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238009/ Cited by 49 (OpenAlex, opens in a new tab)
  4. 17. Raghuram, G. V., Pal, K., Sriram, G., Khan, A., Joshi, R., Jadhav, V., ... & Mittra, I. (2024). Therapeutic interventions on human breast cancer xenografts promote systemic dissemination of oncogenes. Plos one, 19(2), e0298042. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0298042 Cited by 5 (OpenAlex, opens in a new tab)

Impact

Who cites our work

Cited by leading scientists

Authors and affiliations as listed on each citing paper. Select a name to open that paper.

Our work has been cited in

By researchers at

Names and logos identify where citing papers appeared or where their authors work; they do not imply endorsement.

Featured citing papers

See the full list of citations →

Source: OpenAlex, October 2026. Includes 47 citations by the laboratory’s own later papers.