Radiation‐Induced Liver Disease: From Mechanistic Paradigms to Systems‐Level Prevention and Management

ABSTRACT Radiation‐induced liver disease (RILD) is a critical dose‐limiting toxicity of abdominal tumour radiotherapy. Non‐classical RILD (ncRILD)—characterized by poorly understood mechanisms, a paucity of biomarkers and limited therapeutic strategies—poses an urgent clinical challenge. Building on a systematic review of differences in clinical phenotypes, pathological processes and established mechanisms such as reactive oxygen species (ROS) overload‐mediated DNA damage between classical and ncRILD, this review provides a comprehensive integration and in‐depth analysis of three emerging pathogenic mechanisms: (1) m 6 A epigenetic modification drives innate immune dysregulation through the ALKBH5–HMGB1–STING axis (functionally validated in RILD models); (2) epidermal growth factor receptor (EGFR) emerges as a top‐ranked hub protein in irradiated liver sinusoidal endothelial cells, suggesting a reversal from a protective signal to a pro‐injury switch (proteomic evidence; functional validation pending); and (3) a proposed crosstalk among taurine metabolic dysregulation, ferroptosis and disulfidptosis, which may clarify the role of metabolic cell death in RILD progression (theoretical hypothesis). The review further analyzes bidirectional interactions between RILD and the liver microenvironment, tumour microenvironment and immune response and constructs an end‐to‐end management framework encompassing pharmacological prevention and treatment, precision radiotherapy and the three‐tier prevention hierarchy, refining the existing expert‐guidance‐based system. It also evaluates the translational potential of METTL3 inhibitors and liver sinusoid‐targeted interventions for hepatoprotection, and taurine transporter (TAUT) blockade for tumour radiosensitization. Finally, this review highlights that integrating liver‐on‐a‐chip technology, high‐throughput omics and artificial intelligence may drive a paradigm shift in RILD research from ‘post‐injury response’ to full‐spectrum precision prevention and management.