Melatonin ameliorates renal fibrosis by disrupting the DANCR/QK-mediated stabilization of MALAT1 and inhibiting Galectin-3-dependent macrophage polarization

Renal fibrosis drives kidney dysfunction in chronic kidney disease via inflammation, oxidative stress, and fibroblast activation. Deciphering its mechanisms is vital for antifibrotic therapy. A mouse model of renal fibrosis was established via unilateral ureteral obstruction, with melatonin treatment administered. Exosomes from human kidney 2 (HK-2) cells were characterized and co-cultured with phorbol 12-myristate 13-acetate (PMA)-induced M0 macrophages. Macrophage polarization was analyzed via flow cytometry. Gene‑interaction studies were performed, including ribonucleic acid (RNA) immunoprecipitation, pull-down, and luciferase reporter assays. Melatonin treatment decreased metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression in TGF‑β1‑treated HK‑2 cells, alleviated collagen deposition, and improved renal function in vivo. Mechanistically, melatonin disrupted the interaction between differentiation antagonizing non-protein coding RNA (DANCR) and the RNA‑binding protein quaking (QK), thereby destabilizing MALAT1 to downregulate Galectin‑3, which in turn inhibited both M1/M2 macrophage polarization. HK‑2‑derived exosomal MALAT1 was transferred to macrophages, promoting polarization, and administration of MALAT1‑overexpressing exosomes abolished melatonin’s protective effects in vivo. Melatonin destabilizes MALAT1 by suppressing DANCR-associated QK, thereby reducing Galectin-3 to restrain macrophage polarization and mitigate renal fibrosis. Several limitations exist: a single acute animal model, lack of macrophage-specific MALAT1 knockout mice, and absence of clinical validation.