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

Brigitte DRÉNO1 Isabelle BENOIT2 Eric PERRIER2 Miroslav RADMAN3

1 INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302/EMR6001, Nantes Université, Nantes, France

2 NAOS-ILS, Aix-en-Provence, France,

3 Mediterranean Institute for Life Sciences, Split, Croatia, Naos Institute for Life Sciences, Aix-en-Provence, France, Université R.-Descartes Paris-5, Faculté de Médecine, INSERM U1, Paris, France

Reprints: Brigitte Dréno<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。>

Isabelle Benoit <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。>

Eric Perrier <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。>

Skin aging is associated with a progressive decline in physiological functions, skin cancers and, ultimately, death. It may be categorized as intrinsic or extrinsic, whereby intrinsic aging is attributed to chrono-logical and genetic factors. At the molecular level, skin aging involves changes in protein conformation and function. The skin proteome changes constantly, mainly through carbonylation; an irreversible phenomenon leading to protein accumulation as toxic aggregates that impair cellular physiology and accelerate skin aging. This review details the central role of proteostasis during skin aging and why proteome protection may be a promising approach in mitigating skin aging. A comprehensive literature review of 87 articles focusing on the proteome, proteostasis, proteotoxicity, protein carbonylation, and the impact of the damaged proteome on aging, and in particular skin aging, was conducted. Skin aging is associated with deficiencies in the repair mechanisms of DNA, transcriptional control, mitochondrial function, cell cycle control, apoptosis, cellular metabolism, changes in hormonal levels secondary to toxicity of damaged proteins, and cell-to-cell communication for tissue homeostasis, which are largely controlled by proteins. In this context, a damaged proteome that leads to the loss of proteostasis may be considered as the first step in tissue aging. There is growing evidence that a healthy proteome plays a central role in skin and in maintaining healthy tissues, thus slow-ing down the process of skin aging. Hence, protecting the proteome against oxidative or other damage may be an appropriate strategy to prevent and delay skin aging.

Keywords: proteome, proteostasis, protein carbonylation, skin aging

Beatrice Dyring-Andersen1,2,3,4, Marianne Bengtson Løvendorf5, Fabian Coscia1 , Alberto Santos1 , Line Bruun Pilgaard Møller1 , Ana R. Colaço1 , Lili Niu1 , Michael Bzorek6, Sophia Doll7, Jørgen Lock Andersen8, Rachael A. Clark2, Lone Skov 4, Marcel B. M. Teunissen 9 & Matthias Mann 1,7✉

Human skin provides both physical integrity and immunological protection from the external environment using functionally distinct layers, cell types and extracellular matrix. Despite its central role in human health and disease, the constituent proteins of skin have not been systematically characterized. Here, we combine advanced tissue dissection methods, flow cytometry and state-of-the-art proteomics to describe a spatially-resolved quantitative pro-teomic atlas of human skin. We quantify 10,701 proteins as a function of their spatial location and cellular origin. The resulting protein atlas and our initial data analyses demonstrate the value of proteomics for understanding cell-type diversity within the skin. We describe the quantitative distribution of structural proteins, known and previously undescribed proteins specific to cellular subsets and those with specialized immunological functions such as cytokines and chemokines. We anticipate that this proteomic atlas of human skin will become an essential community resource for basic and translational research (https://skin.science/).

1Novo Nordisk Foundation (NNF) Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 2Department of Dermatology, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA. 3 Leo Foundation Skin Immunology Research Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 4Department of Dermatology and Allergology, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. 5 Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark. 6Department of Surgical Pathology, Zealand University Hospital, Næstved, Denmark. 7Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany. 8Department of Plastic and Breast Surgery, Zealand University Hospital, Roskilde, Denmark. 9Department of Dermatology, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands. ✉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。

Jing Ma1,2, Mengting Liu1,2, Yaochi Wang1,2, Cong Xin1,2, Hui Zhang1,2, Shirui Chen1,2, Xiaodong Zheng1,2, Xuejun Zhang1,2, Fengli Xiao1,2,3 , Sen Yang1,2

1Department of Dermatology of First Affiliated Hospital, and Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China

2 Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, Anhui, China

3 The Center for Scientific Research of Anhui Medical University, Hefei, Anhui, China

Correspondence to: Sen Yang, Fengli Xiao;

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。

Keywords: aging, epidermal proteins, skin rejuvenation and aging, proteome, mass spectrometer

Received: February 25, 2020

Accepted: May 27, 2020

Published:

Copyright: Ma et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Skin aging is a specific manifestation of the physiological aging process that occurs in virtually all organisms In this study, we used data independent acquisition mass spectrometry to perform a comparative analysis of protein expression in volar forearm skin samples from of 20 healthy young and elderly Chinese individuals. Our quantitative proteomic analysis identified a total of 95 differentially expressed proteins (DEPs) in aged skin compared to young skin. Enrichment analyses of these DEPs (57 upregulated and 38 downregulated proteins) based on the GO, KEGG, and KOG databases revealed functional clusters associated with immunity and inflammation, oxidative stress, biosynthesis and metabolism, proteases, cell proliferation, cell differentiation, and apoptosis. We also found that GAPDH, which was downregulated in aged skin samples, was the top hub gene in a protein-protein interaction network analysis. Some of the DEPs identified herein had been previously correlated with aging of the skin and other organs, while others may represent novel age-related entities. Our non-invasive proteomics analysis of human epidermal proteins may guide future research on skin aging to help develop treatments for age-related skin conditions and rejuvenation.