PPFIA4 (liprin-α4) is a scaffold protein encoded on chromosome 1.1 that belongs to the PPFIA family of kinesin-cargo linkers 1. The protein contains PFIH and SAM domains enabling binding to LAR subfamily protein tyrosine phosphatases and PPFIBP family proteins 1. Structurally, PPFIA4 lacks the C-terminal GRIP-binding domain present in other PPFIA family members 1. Beyond canonical focal adhesion regulation, PPFIA4 functions in mitochondrial metabolism and cellular stress response. In cancer cells, PPFIA4 localizes to mitochondria where it binds and phosphorylates MTHFD2, enhancing one-carbon metabolism and NADPH synthesis to protect against metabolic stress 2. PPFIA4 similarly promotes glucose metabolic reprogramming in response to hypoxia via HIF1α signaling 3. In endothelial cells, PPFIA4 maintains mitochondrial homeostasis and blood-brain barrier integrity, with its mRNA stability regulated by DDX24 4. Clinically, PPFIA4 upregulation associates with aggressive cancer phenotypes across multiple malignancies. In castration-resistant prostate cancer, colorectal cancer, esophageal cancer, and ovarian cancer, PPFIA4 promotes cell proliferation, migration, glycolysis, and poor patient survival 2, 5, 6, 7, 3. Additionally, PPFIA4 DNA methylation status predicts individual therapeutic responses to the antidepressant paroxetine in major depressive disorder 8.