Objective <p>This studyaims to systematically elucidate the mechanisms underlying hematologic toxicity in ²²⁵Ac-PSMA-617 treatment for metastatic castration-resistant prostate cancer (mCRPC), establish a clinical risk stratification framework, and propose an integrated management strategy to optimize the therapeutic safety margin and efficacy. </p> Methods <p>By&#xa0;integrating and analyzing existing clinical and mechanistic research evidence, a “triple-hit” toxicity mechanism model was proposed. Based on this, key risk factors were identified, risk stratification criteria were established, and a structured clinical management pathway encompassing prevention, monitoring, and intervention was developed.</p> Results <p>The hematologic toxicity of ²²⁵Ac-PSMA-617. results from the synergistic effects of direct α-particle damage, tumor microenvironment(TME)-mediated bone marrow function hijacking, and cumulative depletion of bone marrow reserve. Based on this, we established baseline bone marrow tumor burden, prior treatment history, and hematopoietic function as core risk factors, and proposed stratification criteria for low, intermediate, and high-risk groups along with corresponding differential monitoring and intervention strategies.</p> Conclusion <p>A&#xa0;thorough understanding of the triple-hit mechanism and implementation of risk stratification management facilitate safer and more effective application of ²²⁵Ac-PSMA-617 in the treatment of mCRPC. Future efforts should focus on expanding the therapeutic window of this therapy through individualized dosing, optimization of combination therapies, and development of multidimensional biomarkers.</p>