Beyond oxidative stress: Emerging molecular mechanisms and translational perspectives in environmental toxicant-induced hematotoxicity

Abstract

Background: Environmental toxicants, including heavy metals, pesticides, particulate air pollutants, per- and polyfluoroalkyl substances (PFAS), and microplastics, are increasingly recognized as major contributors to hematological disorders. Although oxidative stress has traditionally been regarded as the principal mechanism underlying environmental toxicant-induced hematotoxicity, emerging evidence suggests that additional molecular pathways contribute substantially to hematopoietic injury. This review examines the evolving molecular mechanisms of environmental toxicant-induced hematotoxicity beyond the conventional oxidative stress paradigm and explores their translational implications. Methods: Literature was retrieved from PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar and synthesized through a structured narrative review. Evidence published primarily between 2020 and 2026 was critically evaluated and organized into thematic areas including oxidative stress, mitochondrial dysfunction, ferroptosis, pyroptosis, epigenetic reprogramming, immunometabolic dysregulation, hematopoietic stem-cell dysfunction, biomarker discovery, multi-omics technologies, artificial intelligence, and precision hematology. Findings: Environmental toxicant-induced hematotoxicity is mediated by a complex network of interacting molecular pathways rather than oxidative stress alone. Emerging evidence highlights important roles for mitochondrial dysfunction, ferroptosis, pyroptosis, epigenetic reprogramming, immunometabolic dysregulation, and hematopoietic stem-cell (HSC) impairment in regulating blood-cell homeostasis and bone marrow integrity. These pathways interact extensively with oxidative stress and contribute to disease heterogeneity, chronic toxicity, and variable clinical outcomes. Advances in multi-omics technologies and artificial intelligence further provide opportunities for biomarker discovery, improved risk assessment, and early disease detection. Conclusion: Environmental toxicant-induced hematotoxicity should be viewed as a systems-level disorder arising from coordinated interactions among multiple molecular pathways. Integrating mechanistic insights with multi-omics technologies, artificial intelligence (AI), and precision hematology may improve disease prediction, biomarker development, early diagnosis, and targeted intervention strategies. Novelty/Originality of this article: This review moves beyond the traditional oxidative stress paradigm by integrating emerging molecular mechanisms into a systems hematotoxicology framework for understanding environmental toxicant-induced hematological injury. It synthesizes evidence on mitochondrial dysfunction, ferroptosis, pyroptosis, epigenetic reprogramming, immunometabolic dysregulation, and hematopoietic stem-cell dysfunction while highlighting their translational relevance for biomarker discovery, multi-omics research, artificial intelligence, and precision hematology. This integrated perspective remains largely absent from conventional reviews that examine these mechanisms independently.