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Unraveling the molecular landscape of chronic radiation injury: From oxidative stress signaling to translational modeling (Review)

  • Authors:
    • Zhenjun Xi
    • Xiaodong Li
    • Chunhui Yang
    • Li Wang
    • Jingxin Mao
    • Qianqian Liu
    • Chang Liu
    • Qian Li
    • Yuanfang Hou
    • Jie Wan
    • Chengzhuo Yang
    • Feiji Sun
    • Chao Yu
    • Miao Wang
    • Baocheng Yuan
    • Yongsheng Liu
    • Qing Hu
    • Li Zhang
    • Xuemei Li
    • Xiaobing Li
  • View Affiliations / Copyright

    Affiliations: Science and Technology Industry Development Center, Chongqing Medical and Pharmaceutical College, Chongqing 401331, P.R. China, Department of Nephrology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510150, P.R. China, Department of Science and Education, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing 400060, P.R. China, Department of Occupational Disease and Poisoning Medicine, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing 400060, P.R. China, Special Medical Department, Daping Hospital, Army Medical University, Chongqing 400042, P.R. China, Department of Rehabilitation Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China, Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing 400060, P.R. China, Department of Pediatrics, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing 400060, P.R. China, Department of Neurology, National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
    Copyright: © Xi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 192
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    Published online on: May 19, 2026
       https://doi.org/10.3892/ijmm.2026.5863
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Abstract

The expanding footprint of human radiation exposure, driven by advances in interventional diagnostics, the resurgence of the nuclear industry and the deep‑space exploration, has necessitated a paradigm shift from understanding acute syndromes to the biological effects of chronic, low‑dose‑rate irradiation. Unlike acute injury, chronic radiation injury (CRI) is a distinct biological entity characterized by the progressive accumulation of sublethal damage, niche remodeling and the propagation of the senescence‑associated secretory phenotype, which collectively drive systemic inflammaging. Deciphering these non‑linear dose‑response dynamics requires high‑fidelity animal models that deconstruct mechanisms often obscured by latency in human epidemiological studies. The present review critically synthesizes the methodological evolution of CRI modeling, contrasting continuous external beam paradigms with internal radionuclide contamination systems. The present study aimed to summarize the pathophysiology of multi‑organ exhaustion, specifically detailing the mechanisms of hematopoietic niche senescence, pulmonary fibrosis and stochastic carcinogenesis, and propose a multidimensional validation framework integrating deep phenotyping, digital pathology and circulating biomarkers to establish rigorous construct validity. Finally, the present study aimed to bridge the translational gap by aligning preclinical screening with the Food and Drug Administration Animal Rule‑a regulatory pathway permitting the approval of medical countermeasures based on animal efficacy data when human trials are unethical, advocating a future defined by single‑cell spatial omics and artificial intelligence‑driven precision radioprotection.
View Figures

Figure 1

Distinction between ARS and CRI:
Dose-rate-dependent temporal and pathobiological divergence.
Schematic of the radiobiological trajectories underlying ARS and
CRI as a function of dose rate, exposure pattern and temporal
evolution. ARS results from HD or HDR irradiation, characterized by
immediate energy deposition over hours to days, leading to
apoptosis and necrosis, rapid tissue ablation, bone marrow failure
and pronounced deterministic effects, such as gastrointestinal
mucosal breakdown, cutaneous burns and neurovascular
collapse-driven by acute cytokine release and systemic inflammatory
responses. CRI arises from prolonged LDR or environmental exposure
over months to years, typically delivered in a continuous or
fractionated manner. This favors the accumulation of sublethal DNA
damage, cellular senescence with activation of the SASP and
persistent genomic instability. These processes promote chronic
oxidative stress, tissue remodeling, progressive fibrosis, immune
dysregulation and increased stochastic risks of carcinogenesis.
ARS, acute radiation syndrome; CRI, chronic radiation injury; HDR,
high-dose-rate; LDR, low-dose-rate; SASP, senescence-associated
secretory phenotype.

Figure 2

Role of oxidative stress signaling in
mediating chronic radiation-induced systemic toxicity. Molecular
cascades connecting chronic low-dose exposure to multi-organ
pathology. Prolonged exposure to low-dose ionizing radiation drives
the sustained accumulation of ROS, establishing a state of
persistent oxidative stress and cumulative DNA damage. This
oxidative burden serves as a master switch, concurrently activating
distinct stress-response pathways: Upregulation of p53 signaling
mediates cell cycle arrest and senescence, primarily contributing
to hematopoietic stem cell exhaustion and immune dysfunction.
Chronic activation of NF-κB propagates a pro-inflammatory
microenvironment, driving tissue fibrosis and stochastic
tumorigenesis. These molecular perturbations culminate in
widespread cellular dysfunction, manifesting as clinical injury
across the hematopoietic, immune, nervous and reproductive systems.
ROS, reactive oxygen species.

Figure 3

Chronic radiation injury:
Organ-specific pathology and molecular drivers. Pathophysiological
sequelae of protracted low-dose-rate exposure compared to acute
injury. The hematopoietic compartment acts as the primary most
sensitive biological indicator and early responder to radiation
toxicity. Chronic stress drives HSC exhaustion and remodels the
niche into an adipogenic (fatty marrow) state, leading to
persistent cytopenia and regenerative failure. The immune
microenvironment shifts toward a pro-inflammatory inflammaging
state. Activated macrophages and senescent cells secrete SASP
factors (IL-6, TNF-α) via the cGAS/STING pathway, creating a
tumor-permissive environment. The unifying molecular mechanism
involves a self-perpetuating cycle of mitochondrial dysfunction
(ROS leakage) and genomic instability (γ-H2AX accumulation). This
triggers p53-mediated cell cycle arrest, driving the cell
senescence that underlies systemic tissue dysfunction. The central
nervous system exhibits microglial-mediated neuroinflammation. This
results in synaptic stripping (loss of dendritic spines) in the
hippocampus, manifesting clinically as cognitive rigidity and
behavioral deficit. HSC, hematopoietic stem cell; SASP,
senescence-associated secretory phenotype; TNF, tumor necrosis
factor; ROS, reactive oxygen species; cGAS, cyclic GMP-AMP
synthase; STING, stimulator of interferon genes.

Figure 4

Methodological paradigms for modeling
CRI: External beam irradiation, internal radionuclide exposure and
non-targeted BE. Schematic of the principal experimental strategies
used to model CRI in vivo, highlighting complementary
approaches that capture distinct physical, dosimetric and
biological dimensions of prolonged radiation exposure. (A) External
beam irradiation models. WBI delivers a homogeneous dose to
simulate systemic exposure scenarios such as nuclear accidents or
unshielded occupational environments, enabling assessment of global
hematopoietic and immune failure. PBI, achieved through physical
shielding or image-guided precision platforms, restricts radiation
to selected anatomical regions, allowing organ-specific injury
(lung or brain) to be studied while sparing critical bone marrow
compartments. (B) Internal exposure and radionuclide deposition.
Internal contamination models reproduce biologically realistic
exposure via inhalation, ingestion or wound entry of radionuclides,
followed by tissue-specific deposition (bone, thyroid). These
systems integrate radionuclide biokinetics, effective half-life,
and LET and are indispensable for studying chronic low-dose-rate
exposure and high-LET particle effects that cannot be mimicked by
external beams. (C) RIBE. Non-targeted effects are demonstrated by
intercellular signaling from irradiated target cells to
non-irradiated bystander cells through ROS, cytokines and
exosome-mediated communication, resulting in DNA damage and
persistent stress responses in distal tissue. Collectively, these
paradigms underscore the need for integrated modeling frameworks to
capture the complexity of CRI, encompassing direct energy
deposition, indirect microenvironmental signaling and long-term
systemic consequences. CRI, chronic radiation injury; WBI,
whole-body irradiation; PBI, partial-body irradiation; LET, linear
energy transfer; RIBE, radiation-induced bystander effect; ROS,
reactive oxygen species.

Figure 5

Multilevel assessment hierarchy for
characterizing systemic toxicity and hematopoietic dysfunction in
chronic radiation injury models. Hierarchical strategy for
evaluating the spectrum of radiation-induced injury across
biological dimensions. Basic assessment (systemic health) monitors
macroscopic physiological indicators including body weight
trajectory, nutritional intake and locomotor activity, serving as
early warning signs of functional decline and sickness behavior.
Core assessment (hematological status) surveils the circulating
compartment. Complete blood counts and flow cytometric profiling
are used to identify specific cytopenias and lineage skewing within
immune cell subsets, reflecting bone marrow integrity. Microscopic
assessment (organ architecture) visualizes structural abnormalities
in radiosensitive parenchymal organs (thymus, spleen, kidney).
Histopathological analysis identifies defining morphological
hallmarks, such as organ atrophy, fatty degeneration and the
disruption of cortico-medullary boundaries. Molecular assessment
(mechanistic drivers) assesses underlying biological initiators of
toxicity. Assays for DNA damage (phosphorylated histone H2AX),
oxidative stress and inflammatory cytokine profiles (ELISA) link
observed phenotypic changes to molecular pathology. Collectively,
these integrated assessments provide a high-resolution profile of
exposure-induced dysfunction, bridging molecular mechanisms with
organ-level pathology.

Figure 6

Strategic alignment map for CRI
animal model selection: Balancing mechanistic utility with
translational relevance. Trade-off between experimental throughput
(genetic utility) and physiological similarity to humans (face
validity) when selecting animal models for CRI research. Mice offer
unparalleled genetic manipulability (transgenic strains) and
high-throughput screening capabilities, serving as the primary
mechanistic workhorse despite lower physiological homology. Rats
provide a balanced platform with larger physiological volumes
suitable for surgical interventions and serial sampling, bridging
the gap between molecular discovery and clinical relevance. Large
animal models (minipigs and NHPs) exhibit high anatomical and
immunological similarities that are key for pivotal preclinical
validation. Minipigs serve as anatomical proxies for cutaneous and
GI injury, while NHPs are the gold standard for assessing complex
neuro-cognitive and immune outcomes. CRI, chronic radiation injury;
GI, gastrointestinal; NHP, non-human primate.

Figure 7

Multidimensional, closed-loop
framework for establishing construct validity in chronic radiation
injury models. Physiological assessment captures early systemic
manifestations of radiation stress through longitudinal monitoring
of the frailty index (body weight, activity levels, feeding
behavior), distinguishing chronic wasting from acute transient
toxicity. Hematological surveillance provides a dynamic readout of
bone marrow integrity. Analysis focuses on lineage skewing (myeloid
bias) and immunosenescence (T cell exhaustion) via flow cytometry,
rather than simple pancytopenia. Histopathological architecture
defines irreversible tissue remodeling at the microscopic level,
characterized by organ atrophy, marrow adipogenesis and fibrotic
degeneration quantified by digital pathology. Molecular
interrogation establishes the mechanistic root of injury. This
includes the detection of genomic instability (phosphorylated
histone H2AX), oxidative stress and the systemic
senescence-associated secretory phenotype signature (elevated IL-6,
TGF-β) that drives the pathology. Macroscopic phenotypic
abnormalities can be traced back to underlying molecular
dysfunction. This closed-loop assessment confirms that the model
recapitulates the progressive, non-linear pathology of human
chronic radiation exposure.

Figure 8

Translational roadmap: Bridging
preclinical modeling and precision radioprotection. Validated
animal models (minipigs, humanized mice) serve as the operational
core for screening medical countermeasures. These high-fidelity
systems provide efficacy data required by the FDA animal rule,
bypassing the ethical constraints of human testing. Integration of
spatial transcriptomics and artificial intelligence-driven deep
phenotyping enhances the sensitivity of these models, allowing
detection of subtle pathologies and the mapping of mechanism-based
targets (such as senolytics). By leveraging digital twins (in
silico models constructed from large multi-omics datasets),
researchers can simulate long-term outcomes and design personalized
radiation health passports for diverse risk groups, ranging from
nuclear workers to deep-space astronauts. FDA, Food and Drug
Administration; LDR, low-dose-rate.
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Xi Z, Li X, Yang C, Wang L, Mao J, Liu Q, Liu C, Li Q, Hou Y, Wan J, Wan J, et al: Unraveling the molecular landscape of chronic radiation injury: From oxidative stress signaling to translational modeling (Review). Int J Mol Med 58: 192, 2026.
APA
Xi, Z., Li, X., Yang, C., Wang, L., Mao, J., Liu, Q. ... Li, X. (2026). Unraveling the molecular landscape of chronic radiation injury: From oxidative stress signaling to translational modeling (Review). International Journal of Molecular Medicine, 58, 192. https://doi.org/10.3892/ijmm.2026.5863
MLA
Xi, Z., Li, X., Yang, C., Wang, L., Mao, J., Liu, Q., Liu, C., Li, Q., Hou, Y., Wan, J., Yang, C., Sun, F., Yu, C., Wang, M., Yuan, B., Liu, Y., Hu, Q., Zhang, L., Li, X., Li, X."Unraveling the molecular landscape of chronic radiation injury: From oxidative stress signaling to translational modeling (Review)". International Journal of Molecular Medicine 58.1 (2026): 192.
Chicago
Xi, Z., Li, X., Yang, C., Wang, L., Mao, J., Liu, Q., Liu, C., Li, Q., Hou, Y., Wan, J., Yang, C., Sun, F., Yu, C., Wang, M., Yuan, B., Liu, Y., Hu, Q., Zhang, L., Li, X., Li, X."Unraveling the molecular landscape of chronic radiation injury: From oxidative stress signaling to translational modeling (Review)". International Journal of Molecular Medicine 58, no. 1 (2026): 192. https://doi.org/10.3892/ijmm.2026.5863
Copy and paste a formatted citation
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Spandidos Publications style
Xi Z, Li X, Yang C, Wang L, Mao J, Liu Q, Liu C, Li Q, Hou Y, Wan J, Wan J, et al: Unraveling the molecular landscape of chronic radiation injury: From oxidative stress signaling to translational modeling (Review). Int J Mol Med 58: 192, 2026.
APA
Xi, Z., Li, X., Yang, C., Wang, L., Mao, J., Liu, Q. ... Li, X. (2026). Unraveling the molecular landscape of chronic radiation injury: From oxidative stress signaling to translational modeling (Review). International Journal of Molecular Medicine, 58, 192. https://doi.org/10.3892/ijmm.2026.5863
MLA
Xi, Z., Li, X., Yang, C., Wang, L., Mao, J., Liu, Q., Liu, C., Li, Q., Hou, Y., Wan, J., Yang, C., Sun, F., Yu, C., Wang, M., Yuan, B., Liu, Y., Hu, Q., Zhang, L., Li, X., Li, X."Unraveling the molecular landscape of chronic radiation injury: From oxidative stress signaling to translational modeling (Review)". International Journal of Molecular Medicine 58.1 (2026): 192.
Chicago
Xi, Z., Li, X., Yang, C., Wang, L., Mao, J., Liu, Q., Liu, C., Li, Q., Hou, Y., Wan, J., Yang, C., Sun, F., Yu, C., Wang, M., Yuan, B., Liu, Y., Hu, Q., Zhang, L., Li, X., Li, X."Unraveling the molecular landscape of chronic radiation injury: From oxidative stress signaling to translational modeling (Review)". International Journal of Molecular Medicine 58, no. 1 (2026): 192. https://doi.org/10.3892/ijmm.2026.5863
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