Zsuzsa Muszka 1,2,4 , Viktória Jenei1,3,4, Rebeka Mácsik1 , Evgeniya Mezhonova1 , Silina Diyab1 , Réka Csősz1 , Attila Bácsi1 , Anett Mázló1✉ and Gábor Koncz 1 ✉

Chronic diseases affecting the cardiovascular system, diabetes mellitus, neurodegenerative diseases, and various other organspecific conditions, involve different underlying pathological processes. However, they share common risk factors that contribute to the development and progression of these diseases, including air pollution, hypertension, obesity, high cholesterol levels, smoking and alcoholism. In this review, we aim to explore the connection between four types of diseases with different etiologies and various risk factors. We highlight that the presence of risk factors induces regulated necrotic cell death, leading to the release of damage-associated molecular patterns (DAMPs), ultimately resulting in sterile inflammation. Therefore, DAMP-mediated inflammation may be the link explaining how risk factors can lead to the development and maintenance of chronic diseases. To explore these processes, we summarize the main cell death pathways activated by the most common life-threatening risk factors, the types of released DAMPs and how these events are associated with the pathophysiology of diseases with the highest mortality.

Cell Death and Disease (2025) 16:273 ; https://doi.org/10.1038/s41419-025-07563-7

FACTS

Environmental, physiological or behavioral risk factors can induce regulated necrotic cell death and DAMP production.

DAMP-related sterile inflammation plays a role in the development and progression of cardiovascular diseases, neurodegenerative diseases, diabetes or alcoholic and non-alcoholic liver diseases.

Current anti-inflammatory treatments do not target the root cause of cell death processes and the release of DAMPs.

OPEN QUESTIONS

To what extent can the harmful effects of risk factors be mitigated by regulating necrotic cell death?

To what extent do the DAMP patterns of pathologies associated with sterile inflammation overlap?

In which diseases can drugs targeting the pathomechanism ofsterile inflammation be used, such as drugs that inhibit the effects of regulated cell death or DAMPs?

1 Department of Immunology, Faculty of Medicine, University of Debrecen, Egyetem square 1, 4032 Debrecen, Hungary. 2 Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Egyetem square 1, 4032 Debrecen, Hungary. 3 Gyula Petrányi Doctoral School of Allergy and Clinical Immunology, University of Debrecen, Egyetem square 1, 4032 Debrecen, Hungary. 4 These authors contributed equally: Zsuzsa Muszka, Viktória Jenei. ✉email: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。; 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。 Edited By Massimiliano Agostini