MCF2L (MCF.2 cell line derived transforming sequence like) encodes a guanine nucleotide exchange factor that, contrary to typical family members, does not catalyze guanine nucleotide exchange on CDC42 1. The gene has emerged as a significant genetic susceptibility locus for osteoarthritis, with variants in MCF2L showing robust association with disease risk across large population studies 2. The rs11842874 polymorphism within intron 4 of MCF2L operates as an expression quantitative trait locus (eQTL) in synovial membrane tissue, where the risk-conferring A allele correlates with increased MCF2L expression 3. MCF2L protein is detectable in joint tissues including cartilage, synovial membrane, and infrapatellar fat pad, with tissue-specific differences in expression patterns and transcript isoforms 3. The gene's connection to nerve growth factor (NGF) regulation suggests a role in pain pathways relevant to osteoarthritis pathogenesis 2. Additionally, the antisense long non-coding RNA MCF2L-AS1 has been implicated in various cancers, including hepatocellular carcinoma, ovarian cancer, breast cancer, and lung adenocarcinoma, where it promotes oncogenic behaviors and drug resistance through multiple molecular mechanisms 4567.