Abstract:Hepatic reserve is an important determinant of treatment tolerance and prognosis in patients with hepatocellular carcinoma (HCC). However, currently available assessment systems were largely developed in the eras of hepatectomy and locoregional therapies and may have limited ability to capture dynamic changes in hepatic function and distinguish different patterns of treatment-related liver injury in the era of targeted and immune therapies. This review systematically summarizes commonly used approaches for assessing hepatic reserve and analyzes the major mechanisms underlying hepatic reserve impairment induced by hepatectomy, transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), radiotherapy, molecular targeted therapy, and immune checkpoint inhibitors (ICIs). Different treatment modalities exhibit distinct initiating events and molecular mechanisms. Hepatectomy mainly reduces hepatic reserve through loss of functional liver parenchyma and ischemia-reperfusion injury. TACE causes hepatic injury through a combination of ischemic necrosis and chemotherapy-induced cytotoxicity, whereas HAIC is primarily associated with the direct toxicity of high-concentration chemotherapeutic agents. Tyrosine kinase inhibitors may induce hepatic injury through mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress, and impaired bile acid transport, while anti-vascular endothelial growth factor (VEGF) monoclonal antibodies mainly cause indirect injury through hepatic sinusoidal endothelial and microcirculatory disturbances. In contrast, immune checkpoint inhibitor-related immune-mediated liver injury is characterized predominantly by aberrant T-cell activation and immune-inflammatory responses and differs mechanistically from conventional drug-induced liver injury. Based on these findings, we further characterize four high-risk phenotypes, including high baseline liver disease activity, immune susceptibility, advanced age with low hepatic reserve, and cumulative hepatic injury after conversion therapy. Comprehensive prevention and management strategies are proposed, including individualized treatment selection, dynamic monitoring during the peri-treatment period, and risk-adapted hepatoprotective interventions. In conclusion, treatment-associated hepatic reserve impairment in HCC is heterogeneous according to both treatment modality and patient characteristics. Multidimensional dynamic assessment and mechanism-based risk stratification may facilitate a better balance between antitumor efficacy and hepatic safety.