LHFPL3 is a tetraspan membrane protein located on chromosome 7 with roles in both normal physiology and disease pathogenesis. In normal tissue, LHFPL3 is associated with sensory perception and plasma membrane localization [NCBI annotation]. The LHFPL3 locus generates multiple functionally distinct transcripts, including protein-coding LHFPL3 and long non-coding RNAs (lncRNAs) LHFPL3-AS1 and LHFPL3-AS2, each with distinct biological roles. In cancer biology, the protein-coding LHFPL3 is upregulated in glioblastoma and promotes tumor progression; miR-218-5p suppresses glioma cell proliferation and invasion by directly targeting LHFPL3 mRNA 1. LHFPL3 also serves as a fusion partner in NTRK-fused gliomas, where NTRK2-LHFPL3 fusion proteins are found in pediatric and adult diffuse gliomas and represent targets for TRK inhibitor therapy 2. The LHFPL3-AS1 lncRNA promotes melanoma tumorigenesis through the miR-181a-5p/BCL2 pathway 3 and via a positive feedback loop with miR-580-3p/STAT3 signaling 4. Conversely, LHFPL3-AS2 lncRNA functions as a tumor suppressor: it is downregulated in non-small cell lung cancer and correlates with improved survival 5, is reduced in lung adenocarcinoma with prognostic significance 6, promotes esophageal squamous cell carcinoma progression under starvation conditions 7, and its reduction in Crohn disease impairs epithelial polarity and proliferation 8.