LncRNA FLJ20021 Restrains Fibroblast Senescence and Matrix Remodeling in Pelvic Organ Prolapse by Promoting XRCC6-Dependent ADI1 Transcription.

Pelvic-organ prolapse (POP) is an age-associated disorder that is often accompanied by uterosacral ligament (USL) weakening and extracellular matrix (ECM) degradation; however, the upstream regulators linking fibroblast aging to ECM remodeling remain incompletely defined. Here, we identify an uncharacterized long non-coding RNA (lncRNA), FLJ20021, as significantly downregulated in POP-derived USL tissues and primary human uterosacral-ligament fibroblasts (hUSLFs) compared with non-POP controls. FLJ20021 depletion reduces hUSLF proliferation and increases apoptosis and senescence, whereas FLJ20021 overexpression reverses these effects and shifts ECM-related markers toward a matrix-preserving profile. Mechanistically, FLJ20021 directly binds the DNA-binding domain (DBD) of X-ray repair cross-complementing 6 (XRCC6), facilitates XRCC6 occupancy at the ADI1 promoter, and promotes XRCC6-dependent ADI1 transcription. Gain- and loss-of-function as well as rescue experiments place XRCC6 downstream of FLJ20021 and support ADI1 as a required effector for FLJ20021-dependent cellular and ECM-related phenotypes. In POP-relevant murine injury models, XRCC6 and ADI1 are coordinately reduced with ECM-marker imbalance, and FLJ20021 overexpression partially restores ADI1 and ECM-related readouts in vivo. Together, these data support a model in which FLJ20021 interacts with XRCC6 to regulate ADI1 expression, thereby linking fibroblast-fate control to ECM homeostasis and providing mechanistic insight into POP-associated tissue degeneration.