Cited by 1Liver physiology and pathologyEffects of Radiation ExposureDrug-Induced Hepatotoxicity and Protection

Single-cell transcriptome sequencing reveals hepatocyte heterogeneity in response to radiation-induced liver injury and regeneration

Li, Liqing, Wu, Qiaoyuan, Lin, Zhitao, Liang, Shixiong, Fu, Qingguo, Wei, Yuxin, Wang, Bofei, Su, Tingshi·2026·Radiotherapy and Oncology

Abstract

Background and purpose Radiation-induced liver injury (RILI) presents a significant constraint on radiotherapy efficacy for hepatic malignancies, yet its underlying mechanisms remain poorly defined. Materials and methods Employing integrated single-cell and single-nucleus RNA sequencing in a rat model receiving 3/4 vol partial liver irradiation (25 Gy), combined with proteomic profiling of human liver tissues, we delineated the spatiotemporal dynamics of hepatocyte responses to RILI. Results Hepatocyte subpopulations exhibited a compartmentalized division of labor: midzonal (zone 2) hepatocytes were characterized by transient proliferation in conjunction with coagulation factors (Fga/Fgb/Fgg) and ERK signaling, whereas periportal and pericentral (zone 1and 3) hepatocytes were characterized by p53-mediated cell cycle restraint and metabolic adaptation involving PPARα-YAP1-TEAD1 signaling. Trajectory analysis supported zone 2 hepatocytes as the primary source for repopulating damaged zone 1/3 compartments, with periportal regions (zone 1) replenishing first. Notably, pericentral (zone 3) hepatocytes demonstrated heightened vulnerability, manifesting late-stage hypertrophy and S-phase arrest. Interzonal crosstalk, including VEGFA-KDR signaling from zone 1/3 that was associated with zone 2 vascular remodeling and HGF-MET/GAS6-MERTK pathways that may coordinate regeneration and survival, may further contribute to repair. Critically, proteomic profiling of irradiated human liver tissues validated conserved activation of p53, coagulation, ERK, and PPAR/YAP pathways. Conclusion Our findings unveil a sophisticated spatial paradigm of liver regeneration following radiation injury, wherein spatially partitioned hepatocyte subpopulations deploy compartmentalized repair programs to balance proliferative efficiency and metabolic adaptation, suggesting potential new targets for therapeutic intervention against RILI.

Integrity signals

Registry

Crossref · 10.1016/j.radonc.2025.111225

Cites

63 of 63 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Cites

Flagged first, then by citations

Cited by

Still being checked.

Authors
Li, L., Wu, Q., Lin, Z., Liang, S., Fu, Q., Wei, Y., Wang, B., & Su, T.
Affiliations
  • Guangxi Medical University (CN)
  • The University of Texas MD Anderson Cancer Center (US)
Corresponding author
Wang, Bofei
Venue
Radiotherapy and Oncology
Publisher
Elsevier BV
Published
2026-01
Volume
214
Pages
111225
ISSN
0167-8140 (ISSN-L)
OpenAlex
W4415531814
Cited by
1
References
63
Citations by year
2026: 1
FWCI
0.50
Type
journal article
Language
en
Open access
closed
Locations
  • Radiotherapy and Oncology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Bagui Scholars Program of Guangxi Zhuang Autonomous Region
  • National Natural Science Foundation of China (82360630, 81903257)
  • Guangxi Medical University
  • Natural Science Foundation of Guangxi Province (2020GXNSFAA297171)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
radiation-induced liver injury, hepatocyte heterogeneity, liver regeneration, hepatocyte subpopulations, liver zonation, p53, ERK signaling, coagulation factors, HGF/MET pathway, hepatocyte proliferation, metabolic adaptation, radiotherapy toxicity
MeSH terms
Animals, Humans, Liver, Liver Regeneration, Male, Radiation Injuries, Hepatocytes, Proteomics, Rats, Single-Cell Analysis, Transcriptome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review