HSPA4 is a heat shock protein 70 (HSP70) family member that functions as a nucleotide exchange factor for HSP70 chaperones, facilitating protein folding and quality control 1. Beyond canonical chaperone roles, HSPA4 binds non-coding RNAs transcribed by RNA polymerase III, regulating tRNA biogenesis and gene transcription 2. Mechanistically, HSPA4 restrains transferrin in dopaminergic neurons, preventing ferroptosis by blocking extracellular iron uptake 3. Clinically, HSPA4 dysfunction has significant disease implications. HSPA4 knockout mice develop cardiac hypertrophy and fibrosis due to misfolded protein accumulation 1. In gastric cancer, HSPA4 upregulation promotes immune evasion via the ALKBH5/CD58 axis, impairing CD8+ T cell cytotoxicity and predicting poor prognosis in surgery-only patients, though it correlates with immunotherapy response 4. Breast cancer cells exploit tumor-educated B cells producing anti-HSPA4 IgG, which activates HSPA4-ITGB5 signaling for lymph node metastasis 5. In Parkinson's disease, HSPA4 overexpression alleviates dopaminergic neurodegeneration 3. Frameshift mutations in HSPA4 occur in microsatellite-unstable gastric and colorectal cancers 6. Cerebrospinal fluid HSPA4 levels correlate with Alzheimer's disease biomarkers 7, while HSPA4 negatively regulates mesenchymal stem cell osteogenic differentiation via miR-1287-5p 8.