{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMCF2L has emerged as an important gene implicated in osteoarthritis susceptibility. Genome‐wide association studies have identified risk variants within MCF2L—especially a cluster in intron 4—that are significantly associated with the development of osteoarthritis. These variants not only confer an increased risk for joint degeneration but also appear to influence local signaling pathways, such as the regulation of nerve growth factor (NGF), which is known to modulate pain and joint function. Such associations have been corroborated across large patient cohorts and multiple OA studies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, MCF2L encodes a guanine nucleotide exchange factor (GEF), historically referred to as DBS, that plays a key role in the activation of Rho family GTPases. Studies in fibroblasts and other cell types have revealed that the protein interacts directly with activated Rac1 via its pleckstrin homology domain, suggesting it acts as both an effector and a regulator to influence pathways mediated by Rac1 and RhoA. Notably, a rare non‐synonymous variant within the DH domain of MCF2L was found to impair its ability to activate these GTPases, leading to defective stress fiber formation and potentially contributing to the pathology of premature cardiovascular disease. Together, these findings underscore the functional role of MCF2L in modulating cytoskeletal dynamics and receptor trafficking."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond joint and vascular pathologies, aberrant expression of MCF2L has been linked to cancer progression and altered cell survival. Elevated levels of MCF2L were observed in gemcitabine‐resistant pancreatic cancer cells, suggesting a role in chemoresistance by modulating survival signaling pathways. In parallel, regulatory non‐coding RNAs—such as miR‑140‑3p and the long non‑coding RNA MCF2L‑AS1—have been shown to impact cell viability and differentiation in osteoblasts and colorectal cancer cells through direct targeting of MCF2L. These studies indicate that MCF2L’s function extends from cytoskeletal regulation to the modulation of key cell fate decisions in diverse disease contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Aaron G Day-Williams, Lorraine Southam, Kalliope Panoutsopoulou, et al. 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