2025.11.17
Hematotoxicity is a crucial safety concern that cannot be ignored in the process of drug development, exerting a profound impact on clinical therapeutic effects and patient prognosis.
Hematotoxicity refers to the harmful effects of chemicals or drugs on the hematopoietic system, manifested as a reduction in the number of blood cells or abnormal cell function. This type of toxicity has become a serious yet often overlooked issue in the drug discovery process [1]. Hematotoxicity can present as various cytopenias, including neutropenia, thrombocytopenia, and anemia [2]. In the field of cancer treatment, drug-induced cytopenias not only worsen clinical outcomes but also hinder the effective treatment of cancer [2]. Notably, hematotoxicity is associated not only with traditional cytotoxic chemotherapeutic drugs but also with novel targeted small-molecule drugs [2].
The mechanisms of drug-induced hematotoxicity are complex and diverse, and current research has revealed a variety of key pathways:
Mitochondrial Dysfunction Mechanism: Recent studies have shown that drug-induced mitochondrial dysfunction is one of the important mechanisms underlying hematotoxicity. Network- and structure-based systems pharmacology approaches have deepened our understanding of this mechanism [3]. Implementing a stratified systems pharmacology approach during the preclinical drug development phase helps detect the adverse effects of drugs on mitochondria [3].
Ferroptosis Pathway: Studies have demonstrated that ferroptosis plays a key role in benzene-induced hematotoxicity. Rats exposed to benzene exhibit a reduction in peripheral blood cell counts, which is associated with the activation of the ferroptosis pathway [4]. UBE2L3 may be involved in benzene-induced early hematopoietic injury by regulating the autophagy-dependent ferroptosis signaling pathway [5].
Inflammatory Response and Glycolysis: PKM2-dependent glycolysis is involved in benzene-induced hematotoxicity by regulating the inflammatory response [6]. Acetylproteomics analysis has revealed the specific mechanism of this process [6].
Abnormal Kinase Signaling Pathway: Studies have found that the hematotoxicity of hematopoietic stem/progenitor cells (HSPCs) induced by hydroquinone (HQ) can be attributed to the activation of the p38 signaling pathway and the inhibition of the Akt signaling pathway mediated by Src kinase [7]. The tyrosine kinase inhibitor SKI-606 may serve as a potential drug to alleviate benzene-induced hematotoxicity [7].
Apoptosis and Autophagy: Cell damage and apoptosis are closely related to hematotoxicity [8], while autophagy-dependent signaling pathways also play a role in hematotoxicity induced by certain chemicals [5].
The main objectives of hematotoxicity research include:
Promote the understanding of early hematotoxicity phenotypes: By studying hematotoxicity induced by chemicals such as benzene, we can enhance the understanding of early toxic phenotypes [9], providing a basis for the early diagnosis of related diseases.
Reveal underlying mechanisms: Research aims to clarify the pathogenesis of benzene-induced hematotoxicity and potential intervention measures [4], particularly exploring the precise impact of lipid deposition on benzene-induced hematotoxicity and its underlying mechanisms [10].
Develop predictive models: Since only a few models are currently available for predicting hematotoxicity [1], research focuses on constructing high-quality datasets and establishing machine learning-based classification models [1], as well as developing novel graph-based deep learning algorithms to evaluate hematotoxicity [1].
Provide a basis for safe medication use: Research lays the foundation for the development of safer antibiotics and improved clinical monitoring through biomarker identification [11], while also helping to understand the mechanisms and risk factors of severe hepatotoxicity caused by novel tumor therapeutic drugs [12].
Develop intervention strategies: Explore drugs that may alleviate hematotoxicity, such as COX-2 inhibitors [13], and evaluate potential therapeutic drugs such as tyrosine kinase inhibitors [7].
Hematotoxicity research involves a variety of evaluation indicators, mainly including:
Blood cell count: Peripheral blood cell count is a basic indicator for evaluating hematotoxicity. Animal models exposed to benzene show a reduction in peripheral blood cell counts [4].
Toxicity grading: The Common Terminology Criteria for Adverse Events (CTCAE) is used to grade hematotoxicity [14], which is a standardized evaluation method in clinical trials.
Specific toxicity types: Focus on Grade 3 or Grade 4 hematotoxicity, including neutropenia (incidence up to 77.22%), thrombocytopenia (29.70%), and anemia (15.84%) [15].
Bone marrow function evaluation: Study the impact of hemophagocytic lymphohistiocytosis-like toxicity (HLH) on bone marrow recovery and cytopenia [14].
Coagulation function: Coagulopathy is defined as evidence of bleeding or abnormal coagulation parameters [14], which is an important aspect of hematotoxicity evaluation.
Novel biomarkers: Explore biomarkers that may be involved in early hematopoietic injury, such as UBE2L3 [5], and metabolism-related biomarkers such as PKM2 [6].
Histopathological changes: Evaluate the pathological changes of hematopoietic tissues such as bone marrow and spleen, which is an important evaluation content in preclinical research.
In the process of drug development, the evaluation of hematotoxicity in the preclinical phase is crucial, involving a variety of experimental methods:
Hematopoietic stem/progenitor cell (HSPCs) research: Used to evaluate the toxic mechanisms of chemicals such as hydroquinone on the hematopoietic system and reveal changes in signaling pathways mediated by Src kinase [7].
Proteomics analysis: For example, acetylproteomics is used to reveal the role of PKM2-dependent glycolysis in benzene-induced hematotoxicity [6].
Research on cell death mechanisms: Including the role of programmed cell death pathways such as ferroptosis [5] and apoptosis [8] in drug-induced toxicity.
Benzene-induced hematotoxicity model: Rats exposed to benzene can establish a typical hematotoxicity model, characterized by a reduction in peripheral blood cell counts [4], which is used to study mechanisms such as ferroptosis.
High-fat diet combined model: A mouse model with moderate lipid accumulation is established through an 8-week high-fat diet to study the correlation between fat content and the severity of benzene-induced hematotoxicity [10].
Drug intervention model: Evaluate the alleviating effect of drugs such as the tyrosine kinase inhibitor SKI-606 on benzene-induced hematotoxicity [7].
Signaling pathway analysis: Study the role of the p38 and Akt signaling pathways in chemical-induced hematotoxicity [7].
Research on the relationship between autophagy and ferroptosis: Verify the role of the autophagy-dependent ferroptosis signaling pathway through molecular biology methods [5].
Inflammatory response assessment: Explore how PKM2-dependent glycolysis participates in hematotoxicity by regulating the inflammatory response [6].
• Machine learning models: Based on a dataset of 759 hematotoxic compounds and 1623 non-hematotoxic compounds, combined with seven machine learning algorithms to construct predictive models [1].
• Graph neural network models: Develop graph-based deep learning algorithms to identify unique structural features of hematotoxic chemicals [1].
• Bone marrow toxicity screening: Develop specific screening methods for the bone marrow toxicity of anticancer drugs [16].
• Efficacy/toxicity balance research: Research on drugs such as AZD5305 to maintain efficacy while reducing hematotoxicity [17].
• Biomarker discovery: Provide novel biomarkers for clinical monitoring [11].
Hematological parameters: Including counts of various blood cells, hemoglobin levels, etc.
Coagulation function testing: Evaluate parameters such as prothrombin time and activated partial thromboplastin time [14].
Bone marrow pathological examination: Evaluate the degree of hematopoietic tissue damage and recovery.
Organ weight and pathology: Changes in hematopoietic-related organs such as the spleen.
Hematotoxicity research is an important component of drug safety evaluation. Through interdisciplinary approaches, it comprehensively evaluates the impact of drugs on the hematopoietic system from the molecular mechanism to the whole-animal level. With the development of new technologies such as machine learning, proteomics, and gene editing, our understanding and predictive ability of hematotoxicity will continue to improve, providing protection for the development of safer drugs.
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