HSPA9 is a mitochondrial Hsp70 chaperone essential for protein quality control, mediating ATP-driven cycles of protein import, folding, and refolding within mitochondria through interaction with the TIM translocase complex. It stabilizes iron-sulfur cluster assembly proteins and regulates erythropoiesis via this pathway. HSPA9 also couples mitochondrial calcium channels at ER-mitochondria contact sites to facilitate calcium-dependent signaling and apoptosis regulation. In the cytosol, it promotes degradation of p53, potentially suppressing cellular senescence and regulating cell proliferation. Extracellular HSPA9 protects cells from membrane attack complex-mediated lysis. Pathogenic HSPA9 variants cause EVEN-PLUS syndrome, characterized by skeletal dysplasia and multi-system abnormalities 1. The gene is downregulated in heart failure, contributing to mitochondrial dysfunction 2. In cancer contexts, HSPA9 dysfunction has emerged as clinically relevant: KEAP1-mediated HSPA9 degradation suppresses breast cancer proliferation 3, while in cervical cancer, METTL3-mediated m6A modification of HSPA9 mRNA stabilizes exosomal mortalin, promoting malignant transformation and senescence suppression 4. In glioblastoma, OMA1 interaction with HSPA9 promotes mitophagy and immune escape via cGAS-STING pathway activation 5. Artesunate induces ferroptosis in gastric cancer by disrupting the TFRC-HSPA9 axis controlling iron homeostasis 6, suggesting therapeutic potential for ferroptosis-inducing drugs. In bladder cancer, MUL1-mediated HSPA9 SUMOylation and mitochondrial export inhibits lymph node metastasis 7.