FAM111B is a serine protease involved in multiple cellular processes critical for genome maintenance and cell survival. Primary Function: FAM111B functions as a serine-type peptidase 1 with roles in DNA repair, cell cycle regulation, and apoptosis 2. The protein localizes to the nucleus, nuclear lamina, and cytoplasm, where it participates in protein-DNA covalent cross-linking repair and replication fork processing 1. Mechanism: FAM111B promotes cancer progression through multiple pathways: it enhances DNA homologous recombination repair while simultaneously promoting chromosome 11 34. In esophageal cancer, FAM111B functions as a protease that degrades GSDMA, promoting tumorigenesis and chemoresistance 5. In hepatocellular carcinoma, FAM111B regulates mitochondrial dynamics by promoting MFN2 ubiquitination, driving mitophagy and drug resistance 6. Disease Relevance: FAM111B mutations cause poikiloderma, hereditary fibrosing (POIKTMP), characterized by poikiloderma, tendon contractures, myopathy, and pulmonary fibrosis 7. Mutations within the protease domain predict increased disease severity and poor prognosis 7. Clinical Significance: FAM111B overexpression is associated with poor cancer prognosis across multiple tumor types and serves as a pan-cancer biomarker 43. FAM111B represents a promising therapeutic target in cancer and fibrotic diseases.