This review demonstrated that the interplay between MMP-2, MMP-9, and their regulators, such as TGF-β1/Smad, PI3K/AKT, and LncRNA-ZNF252P-AS1/miR-15b-5p/BTF3 signaling cascades, involved in the intricate balance governing ECM homeostasis, collectively driving the excessive collagen deposition and altered tissue architecture observed in keloids. The gene discussed is MMP9; the disease is keloid.