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

Background Renal fibrosis drives kidney dysfunction in chronic kidney disease via inflammation, oxidative stress, and fibroblast activation. Deciphering its mechanisms is vital for antifibrotic therapy.Research design and methods 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.Results 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.Conclusion 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.