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‘Reactive oxygen species’ (ROS) is a generic term that defines a wide variety of oxidant molecules with vastly different properties and biological functions that range from signalling to causing cell damage. Consequently, the description of oxidants needs to be chemically precise to translate research on their biological effects into therapeutic benefit in redox medicine. This Expert Recommendation article pinpoints key issues associated with identifying the physiological roles of oxidants, focusing on H2O2 and O2.–. The generic term ROS should not be used to describe specific molecular agents. We also advocate for greater precision in measurement of H2O2, O2.– and other oxidants, along with more specific identification of their signalling targets. Future work should also consider inter-organellar communication and the interactions of redox-sensitive signalling targets within organs and whole organisms, including the contribution of environmental exposures. To achieve these goals, development of tools that enable site-specific and real-time detection and quantification of individual oxidants in cells and model organisms are needed. We also stress that physiological O2 levels should be maintained in cell culture to better mimic in vivo redox reactions associated with specific cell types. Use of precise definitions and analytical tools will help harmonize research among the many scientific disciplines working on the common goal of understanding redox biology.Reactive oxygen species (ROS) comprise a wide variety of oxidant molecules with vastly different properties and biological functions in physiology and in disease. Approaches to characterize oxidants in the in vivo context and identify their specific cellular targets will be required to understand and control the pathophysiological activities of ROS.

The term ‘fibroblast’ often serves as a catch-all for a diverse array of mesenchymal cells, including perivascular cells, stromal progenitor cells and bona fide fibroblasts. Although phenotypically similar, these subpopulations are functionally distinct, maintaining tissue integrity and serving as local progenitor reservoirs. In response to tissue injury, these cells undergo a dynamic fibroblast–myofibroblast transition, marked by extracellular matrix secretion and contraction of actomyosin-based stress fibres. Importantly, whereas transient activation into myofibroblasts aids in tissue repair, persistent activation triggers pathological fibrosis. In this Review, we discuss the roles of mechanical cues, such as tissue stiffness and strain, alongside cell signalling pathways and extracellular matrix ligands in modulating myofibroblast activation and survival. We also highlight the role of epigenetic modifications and myofibroblast memory in physiological and pathological processes. Finally, we discuss potential strategies for therapeutically interfering with these factors and the associated signal transduction pathways to improve the outcome of dysregulated healing.Fibroblasts undergo transient activation into myofibroblasts to restore homeostasis to injured tissues. This Review explores the influence of mechanical cues and epigenetic modifications on (myo)fibroblast activation and memory and discusses potential therapeutic prevention of persistent myofibroblast activation in fibrosis.

Wound healing is a complex process that involves the coordinated actions of many different tissues and cell lineages. It requires tight orchestration of cell migration, proliferation, matrix deposition and remodelling, alongside inflammation and angiogenesis. Whereas small skin wounds heal in days, larger injuries resulting from trauma, acute illness or major surgery can take several weeks to heal, generally leaving behind a fibrotic scar that can impact tissue function. Development of therapeutics to prevent scarring and successfully repair chronic wounds requires a fuller knowledge of the cellular and molecular mechanisms driving wound healing. In this Review, we discuss the current understanding of the different phases of wound healing, from clot formation through re-epithelialization, angiogenesis and subsequent scar deposition. We highlight the contribution of different cell types to skin repair, with emphasis on how both innate and adaptive immune cells in the wound inflammatory response influence classically studied wound cell lineages, including keratinocytes, fibroblasts and endothelial cells, but also some of the less-studied cell lineages such as adipocytes, melanocytes and cutaneous nerves. Finally, we discuss newer approaches and research directions that have the potential to further our understanding of the mechanisms underpinning tissue repair.This Review discusses the complex mechanisms of wound healing — cell migration, matrix remodelling, inflammation and angiogenesis — and the contributions of different cell types, including immune cells, to this process. It also highlights new methodologies that could inform future therapies to prevent scarring and repair chronic wounds.

Oxidation–reduction (redox) reactions are central to the existence of life. Reactive species of oxygen, nitrogen and sulfur mediate redox control of a wide range of essential cellular processes. Yet, excessive levels of oxidants are associated with ageing and many diseases, including cardiological and neurodegenerative diseases, and cancer. Hence, maintaining the fine-tuned steady-state balance of reactive species production and removal is essential. Here, we discuss new insights into the dynamic maintenance of redox homeostasis (that is, redox homeodynamics) and the principles underlying biological redox organization, termed the ‘redox code’. We survey how redox changes result in stress responses by hormesis mechanisms, and how the lifelong cumulative exposure to environmental agents, termed the ‘exposome’, is communicated to cells through redox signals. Better understanding of the molecular and cellular basis of redox biology will guide novel redox medicine approaches aimed at preventing and treating diseases associated with disturbed redox regulation.Oxidation–reduction (redox) reactions involving reactive oxygen, nitrogen and sulfur species are vital for life, but excessive oxidant levels contribute to ageing and diseases. This Review explores cellular dynamics of redox homeostasis, such as responses to oxidative and reductive stresses and intracellular and intercellular redox communication pathways.

The ability of cells to deal with different types of stressful situations in a precise and coordinated manner is key for survival and involves various signalling networks. Over the past 25 years, p38 kinases — in particular, p38α — have been implicated in the cellular response to stress at many levels. These span from environmental and intracellular stresses, such as hyperosmolarity, oxidative stress or DNA damage, to physiological situations that involve important cellular changes such as differentiation. Given that p38α controls a plethora of functions, dysregulation of this pathway has been linked to diseases such as inflammation, immune disorders or cancer, suggesting the possibility that targeting p38α could be of therapeutic interest. In this Review, we discuss the organization of this signalling pathway focusing on the diversity of p38α substrates, their mechanisms and their links to particular cellular functions. We then address how the different cellular responses can be generated depending on the signal received and the cell type, and highlight the roles of this kinase in human physiology and in pathological contexts.p38α — the best-characterized member of the p38 kinase family — is a key mediator of cellular stress responses. p38α is activated by a plethora of signals and functions through a multitude of substrates to regulate different cellular behaviours. Understanding context-dependent p38α signalling provides important insights into p38α roles in physiology and pathology.

Through their many and varied metabolic functions, mitochondria power life. Paradoxically, mitochondria also have a central role in apoptotic cell death. Upon induction of mitochondrial apoptosis, mitochondrial outer membrane permeabilization (MOMP) usually commits a cell to die. Apoptotic signalling downstream of MOMP involves cytochrome c release from mitochondria and subsequent caspase activation. As such, targeting MOMP in order to manipulate cell death holds tremendous therapeutic potential across different diseases, including neurodegenerative diseases, autoimmune disorders and cancer. In this Review, we discuss new insights into how mitochondria regulate apoptotic cell death. Surprisingly, recent data demonstrate that besides eliciting caspase activation, MOMP engages various pro-inflammatory signalling functions. As we highlight, together with new findings demonstrating cell survival following MOMP, this pro-inflammatory role suggests that mitochondria-derived signalling downstream of pro-apoptotic cues may also have non-lethal functions. Finally, we discuss the importance and roles of mitochondria in other forms of regulated cell death, including necroptosis, ferroptosis and pyroptosis. Collectively, these new findings offer exciting, unexplored opportunities to target mitochondrial regulation of cell death for clinical benefit.Mitochondria are key executioners of apoptosis. However, it has recently become clear that beyond driving apoptosis, mitochondria also contribute to pro-inflammatory signalling and other types of regulated cell death. These functions are relevant to disease and could be targeted in the treatment of, for example, degenerative disorders, infection and cancer.

Double-stranded RNA (dsRNA) is associated with most viral infections — it either constitutes the viral genome (in the case of dsRNA viruses) or is generated in host cells during viral replication. Hence, nearly all organisms have the capability of recognizing dsRNA and mounting a response, the primary aim of which is to mitigate the potential infection. In vertebrates, a set of innate immune receptors for dsRNA induce a multitude of cell-intrinsic and cell-extrinsic immune responses upon dsRNA recognition. Notably, recent studies showed that vertebrate cells can accumulate self-derived dsRNAs or dsRNA-like species upon dysregulation of several cellular processes, activating the very same immune pathways as in infected cells. On the one hand, such aberrant immune activation in the absence of infection can lead to pathogenesis of immune disorders, such as Aicardi–Goutières syndrome. On the other hand, the same innate immune reaction can be induced in a controlled setting for a therapeutic benefit, as occurs in immunotherapies. In this Review, we describe mechanisms by which immunostimulatory dsRNAs are generated in mammalian cells, either by viruses or by the host cells, and how cells respond to them, with the focus on recent developments regarding the role of cellular dsRNAs in immune modulation.Double-stranded RNAs (dsRNAs) are recognized by designated cellular sensors to mount an immune response. Although dsRNAs are generally of viral origin, dysregulation of several cellular processes can lead to accumulation of endogenous dsRNAs. These self-derived dsRNAs are often associated with immune disorders, but their immunogenicity can also be exploited for immunotherapy.

Protein handling, modification and folding in the endoplasmic reticulum (ER) are tightly regulated processes that determine cell function, fate and survival. In several tumour types, diverse oncogenic, transcriptional and metabolic abnormalities cooperate to generate hostile microenvironments that disrupt ER homeostasis in malignant and stromal cells, as well as infiltrating leukocytes. These changes provoke a state of persistent ER stress that has been demonstrated to govern multiple pro-tumoural attributes in the cancer cell while dynamically reprogramming the function of innate and adaptive immune cells. Aberrant activation of ER stress sensors and their downstream signalling pathways have therefore emerged as key regulators of tumour growth and metastasis as well as response to chemotherapy, targeted therapies and immunotherapy. In this Review, we discuss the physiological inducers of ER stress in the tumour milieu, the interplay between oncogenic signalling and ER stress response pathways in the cancer cell and the profound immunomodulatory effects of sustained ER stress responses in tumours.The hostile microenvironment of the tumour can disrupt endoplasmic reticulum (ER) homeostasis in cancer cells and infiltrating immune cells to result in a state of ER stress. This Review discusses how ER stress can influence not only the pro-tumoural features of cancer cells but also reprogramme the function of innate and adaptive immune cells, creating vulnerabilities that could be targeted by emerging therapeutic strategies.

Key Points Mitochondria carry out crucial cellular functions such as energy harvesting. They possess their own genome, encoding 13 proteins, although most of the ∼1,200 mitochondrial proteins originate from the nucleus. Therefore, the nucleus and mitochondria have to constantly communicate to adjust their activities in order to ensure cellular homeostasis and adaptation to mitochondrial stress. This communication is defined as mitonuclear communication. The nucleus modulates gene expression and mitochondrial function through anterograde regulation signalling. Conversely, mitochondria can elicit a retrograde response, on the basis of energetic cues, ROS or calcium signalling, that activates the expression of nuclear genes to respond and adapt to those cellular conditions. Proteostatic stress in the mitochondria can initiate many feedback responses, such as the mitochondrial unfolded protein response (UPR mt ), the proteolytic stress response and the heat shock response, which directly modulate nuclear gene expression and are involved in alleviating the stress. In order to induce a more general adaptation to a cellular state, mitochondrial stress can trigger the integrated stress response (ISR), which reduces cytosolic protein synthesis globally and induces the expression of cellular stress response genes. Mitochondrial stress can be signalled to other cells of the organism by extracellular cues, such as the so-called mitokines, to orchestrate the coordinated adaptation of the whole organism to stress. Given their central role in cellular metabolism and in the maintenance of cellular homeostasis, mitochondria are closely involved in the ageing process. Therefore, several mitochondrial stress and mitonuclear communication pathways modulate lifespan across species. As most mitochondrial proteins are encoded in the nucleus, mitochondrial activity requires efficient communication between the nuclear and mitochondrial genomes. This is mediated by nucleus-to-mitochondria (anterograde), mitochondria-to-nucleus (retrograde) and mitonuclear feedback signalling, as well as the integrated stress response and extracellular communication, which regulate homeostasis and, consequently, healthspan and lifespan. Mitochondria participate in crucial cellular processes such as energy harvesting and intermediate metabolism. Although mitochondria possess their own genome — a vestige of their bacterial origins and endosymbiotic evolution — most mitochondrial proteins are encoded in the nucleus. The expression of the mitochondrial proteome hence requires tight coordination between the two genomes to adapt mitochondrial function to the ever-changing cellular milieu. In this Review, we focus on the pathways that coordinate the communication between mitochondria and the nucleus during homeostasis and mitochondrial stress. These pathways include nucleus-to-mitochondria (anterograde) and mitochondria-to-nucleus (retrograde) communication, mitonuclear feedback signalling and proteostasis regulation, the integrated stress response and non-cell-autonomous communication. We discuss how mitonuclear communication safeguards cellular and organismal fitness and regulates lifespan.