The multifaceted role of FAM13A in pulmonary diseases

FAM13A, a lung-enriched gene encoding a protein with a characteristic RhoGAP domain, is increasingly recognized for its pleiotropic roles across multiple lung diseases, including chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), asthma, and lung cancer. Through modulation of Rho and Wnt/β-catenin signaling, FAM13A regulates key cellular processes such as epithelial barrier maintenance, immune homeostasis, and cell-cycle regulation. Notably, FAM13A exhibits context-dependent duality, associated with tissue destruction in COPD while linked to mitigated fibrotic remodeling in PF. In addition, the complexity introduced by multiple splice variants, interspecies expression differences, and environmental dependence poses significant challenges for further mechanistic studies of FAM13A. By emphasizing the opposing roles of FAM13A in COPD versus PF, the non-linear relationships linking single-nucleotide polymorphisms (SNPs), gene expression, signaling pathways, and disease phenotypes, as well as the combined influence of isoform diversity, species differences, and environmental exposures on functional outcomes, this review integrates current genetic, molecular, and functional evidence to provide a mechanistic framework for understanding FAM13A's roles in pulmonary diseases and refines current paradigms with implications for future research and precision medicine.