Melatonin alleviates ferroptosis and rescues osteogenic function in iron-overloaded BMSCs via suppressing NOX4 transcription.

Authors

Cen Luo, Na Sun, Fei Xiong, Jingjing Sun, Jin Jing, Xin Shao, Lei Xi

Published in

Free radical research. Pages 1-18. Aug 12, 2026. Epub Aug 12, 2026.

Abstract

Iron overload‑induced osteoporosis (IOO) is a growing concern, yet the underlying mechanisms remain obscure. Ferroptosis, an iron‑dependent lipid peroxidation‑driven cell death, and NADPH oxidase 4 (NOX4), a major source of reactive oxygen species (ROS), have been implicated separately, but their interplay in bone marrow stromal cells (BMSCs) under iron overload is unknown. Here we investigated whether melatonin, an endogenous indole with antioxidant properties, protects BMSCs from iron overload‑induced ferroptosis and osteogenic dysfunction by regulating NOX4 transcription. BMSCs were exposed to ferric ammonium citrate (FAC, 200 µM) with or without melatonin (100 µM) or the ferroptosis inhibitor ferrostatin‑1 (Fer‑1). FAC suppressed cell viability, elevated Fe²⁺ and ROS, triggered classical ferroptotic mitochondrial damage (shrinkage, cristae loss), and impaired osteogenic differentiation (ALP activity, mineralization, Alp, Runx2, Col1a1, Osterix). Fer‑1 attenuated ROS and mitochondrial injury but did not reduce Fe²⁺ accumulation, confirming ferroptosis downstream of iron loading. Melatonin did not lower Fe²⁺ levels either; however, it effectively quenched ROS, restored mitochondrial ultrastructure, and rescued osteogenic function. Mechanistically, melatonin transcriptionally suppressed NOX4, as evidenced by reduced NOX4 mRNA and diminished NOX4 promoter activity in dual‑luciferase reporter assays, without affecting Fe²⁺ levels. Collectively, melatonin alleviates ferroptosis and restores osteogenesis in iron‑overloaded BMSCs, an effect that is strongly associated with the transcriptional suppression of NOX4, independent of iron chelation. Our findings extend the established NOX4-ferroptosis mechanism to BMSCs and identify, for the first time, transcriptional suppression of NOX4 as a novel mechanism that is strongly indicated to contribute to melatonin's protective effects against iron overload-induced osteogenic dysfunction.

PMID:
42585554
Bibliographic data and abstract were imported from PubMed on 13 Aug 2026.

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