PLEKHF1 (pleckstrin homology and FYVE domain containing 1) is a phosphatidylinositol-binding protein involved in vesicular trafficking and cell death pathways. It localizes to lysosomes and endosomes, where it regulates autophagy and endosome-to-lysosome transport. PLEKHF1 can trigger caspase-independent apoptosis by initiating lysosomal membrane permeabilization and promoting mitochondrial dysfunction through altered membrane permeability 1. The protein enhances PI3K/Akt signaling downstream of IL-4/IL-13 stimulation to promote alternatively activated macrophage (M2) polarization, contributing to pulmonary fibrosis pathogenesis 2. Clinically, PLEKHF1 dysregulation appears relevant to multiple diseases. In osteosarcoma, PLEKHF1 downregulation correlates with metastatic potential, and overexpression suppresses tumor growth and metastasis through mitochondrial dysfunction induction 1. PLEKHF1 was identified as a prognostic biomarker in osteosarcoma survival prediction 3. In dilated cardiomyopathy, PLEKHF1 emerged as one of eight autophagy-related diagnostic biomarkers 4. Additionally, reduced PLEKHF1 expression was identified as a potential diagnostic biomarker in ankylosing spondylitis, with upregulation observed following TNF-α blocker therapy 5. In breast cancer, PLEKHF1 amplification at the 19q12 locus contributes to cancer cell survival 6. PLEKHF1 siRNA-loaded liposomal therapy shows promise for pulmonary fibrosis treatment 2.