HSPA9 is a mitochondrial Hsp70 chaperone essential for protein quality control, executing ATP-dependent cycles of protein folding, refolding, and degradation 123. It facilitates mitochondrial protein import via the TIM complex and plays a critical role in iron-sulfur cluster biogenesis by stabilizing assembly proteins FXN, NFU1, NFS1, and ISCU, thereby regulating erythropoiesis 45. HSPA9 regulates mitochondrial calcium dynamics by coupling ITPR1 and VDAC1 at mitochondria-associated ER membranes, supporting calcium-dependent apoptosis 6. Beyond mitochondria, cytosolic HSPA9 interacts with signaling and apoptotic proteins, potentially regulating cell cycle through TP53 degradation promotion 78. Extracellular HSPA9 provides cytoprotection against membrane attack complex-mediated lysis 9. Disease relevance is substantial: HSPA9 overexpression associates with glioblastoma immune escape through OMA1-mediated mitophagy and cGAS-STING activation 10, breast cancer progression via KEAP1-regulated mitochondrial biogenesis 11, bladder cancer metastasis through MUL1-mediated nuclear translocation 12, and multiple myeloma bortezomib resistance via exosomal transmission and USP1/TRIP13 signaling 1314. HSPA9 elevation predicts adverse prostate cancer outcomes 15, establishing it as a potential biomarker and therapeutic target across multiple malignancies.