The interplay between toxicological mechanisms and redox biology is a critical area of research that underpins our understanding of how various environmental and biological factors influence health outcomes. Reactive oxygen species and other redox-active molecules, collectively called reactive species (RS) are central players in cellular signaling and homeostasis. However, their dysregulation can lead to oxidative stress, resulting in significant cellular damage. Toxicants, whether from environmental exposure or pharmaceutical sources, can profoundly alter redox states and disrupt normal biological functions, leading to a spectrum of adverse health effects.

Exposure to certain toxicants can lead to disease by compromising the body's antioxidant defenses. This disruption may occur through various direct and indirect mechanisms, including the generation of reactive species, interference with metal ion homeostasis, and alterations in gene expression, cellular signaling, antioxidant synthesis pathways and antioxidant activity. As a result, the body's ability to neutralize reactive species diminishes, allowing their accumulation and causing oxidative damage to vital biomolecules such as DNA, proteins, lipids, and carbohydrates. This oxidative stress can lead to mutations, impaired protein function, lipid peroxidation, and the formation of advanced glycation end-products (AGEs). These molecular alterations can trigger a cascade of inflammatory responses, further intensifying cellular damage and fostering chronic inflammation.

This Collection is motivated by the urgent need to integrate insights from toxicology and redox biology to better comprehend the mechanisms underlying toxicity and the biological responses to oxidative stress. Recent studies have revealed novel molecular targets and pathways that mediate the toxic effects of various compounds, highlighting the importance of redox signaling in these processes. By fostering interdisciplinary collaboration among toxicologists, biochemists, and molecular biologists, we aim to stimulate innovative research that addresses current challenges in the field. This Collection seeks to capture the momentum of recent discoveries and facilitate discussions on the implications of these findings for public health and environmental safety.

The purpose of this Collection is to provide a dedicated platform for researchers to share their findings on the mechanistic insights linking toxicology and redox biology. We invite submissions that explore the molecular mechanisms of toxicity, the role of oxidative stress in disease processes, and the potential for redox-based therapeutic strategies. By compiling a diverse array of studies, this Collection aims to enhance our understanding of how toxicants interact with biological systems and inform future research directions in both toxicology and redox biology.

Areas of interest encompass, but are not limited to, chemical analysis and studies conducted through in vitro, in vivo, ex vivo, in silico approaches:

Chemistry of reactive species generation and regulation. Toxicants can drive the overproduction of reactive species by promoting redox cycling or activating redox-active metals, while also weakening antioxidant defenses that normally neutralize these species. This imbalance leads to oxidative stress, a key contributor to cellular damage and disease. Understanding the chemical pathways through which toxicants directly or indirectly generate reactive species is essential for uncovering their role in toxicity and disease mechanisms.

Endogenous molecular targets of toxicants. These include direct interactions with cellular components, such as lipids, proteins, and DNA, as well as indirect effects like the inhibition of antioxidant enzymes or depletion of essential cofactors. Enzymes involved in antioxidant synthesis (e.g., glutathione peroxidase, superoxide dismutase), mitochondrial proteins, metal-binding proteins as well as small molecules (e.g., glutathione, neurotransmitters, cofactors). Toxicants may bind to or modify these targets causing post-translational protein, epigenetic changes, production of pro-inflammatory mediators (e.g., lipid peroxidation and AGE products), or redox modifications of small molecules, impairing their function and further exacerbating oxidative stress.

Toxicant-mediated redox signaling pathways and other oxidative stress mechanisms. These pathways regulate critical cellular functions such as proliferation, apoptosis, and immune responses. Toxicants can alter redox-sensitive transcription factors (e.g., Nrf2, NF-κB), leading to aberrant gene expression and contributing to disease pathogenesis. Such mechanisms compromise the cell’s ability to maintain redox homeostasis which is a complex and a dynamic process. Xenobiotics can modulate redox-sensitive signaling cascades, alter mitochondrial function, activate immune response, influence the expression of detoxifying genes and alter synthesis of endogenous antioxidants. These interactions not only affect cellular resilience to stress but also determine the long-term outcomes of toxicant exposure.

This Collection supports and amplifies research related to SDG 3.

Keywords: toxicology; redox biology; reactive oxygen species; ROS; oxidative stress; free radicals; oxidative damage; disease pathogenesis

Toxicology is undergoing a profound transformation as the field moves beyond reliance on conventional animal testing toward more human-relevant, mechanistically informed, and efficient approaches. New approach methodologies (NAMs), including in vitro systems, omics technologies, computational modeling, in silico prediction, and integrated testing strategies, are increasingly reshaping how chemical hazards are identified, characterized, and interpreted. At the same time, regulatory science is evolving to consider how these tools can be applied in ways that are scientifically robust, transparent, and fit for decision-making. This collection aims to highlight recent advances in the development, evaluation, and application of NAMs across diverse areas of toxicology and regulatory science. We welcome contributions that improve mechanistic understanding of toxicity pathways, support hazard identification and prioritization, refine dose-response assessment, or strengthen exposure-informed risk evaluation. Particular interest is given to studies that demonstrate the regulatory relevance, readiness, interpretability, and limitations of NAM-based approaches in real-world contexts. Topics of interest include, but are not limited to, cell-based and organotypic models, high-throughput screening, transcriptomics and other omics-based profiling, physiologically based kinetic modeling, computational toxicology, artificial intelligence-assisted methods, defined approaches, integrated approaches to testing and assessment, and case studies that support next-generation risk assessment. Submissions addressing validation, uncertainty, reproducibility, data integration, and regulatory translation are also strongly encouraged. By bringing together original research, reviews, perspectives, and methodological advances, this collection seeks to provide a platform for interdisciplinary dialogue on how NAMs can strengthen contemporary toxicology and accelerate the transition toward more predictive, efficient, and human-relevant regulatory practices.

Keywords: New approach methodologies; Regulatory science; Computational toxicology; In vitro toxicology; Omics; High-throughput screening; Physiologically based kinetic modelling; Integrated approaches to testing and assessment; Next-generation risk assessment; Chemical hazard assessment