Xiaoju Liang, Lijun Zhang, Deliang Cheng
Dexamethasone (Dex) causes growth plate injury and growth retardation in children, yet the underlying epigenetic and post-transcriptional mechanisms remain poorly defined. This study addresses this gap by dissecting the MALAT1/miR-124-3p/LPCAT3 axis in Dex-induced chondrocyte ferroptosis. Primary rat growth plate chondrocytes and 2-week-old male Sprague-Dawley rats were treated with Dex. DNA methylation of the MALAT1 promoter was assessed by MSP analysis. Gain- and loss-of-function studies, CCK-8, ferroptosis markers and luciferase reporter assays were performed in vitro. In vivo, tibial growth plate morphology, zone-specific heights, systemic growth parameters and LPCAT3 expression were evaluated. The results showed that Dex reduced chondrocyte viability and suppressed MALAT1 expression in a dose-dependent manner, accompanied by hypermethylation of one CpG islands in the MALAT1 promoter. Treatment with 5-Aza-2'-deoxycytidine (5-Aza) restored MALAT1 expression and reduced methylation levels. MALAT1 overexpression attenuated Dex-induced ferroptosis, as evidenced by decreased Fe²⁺ and MDA levels and restored SLC7A11 and Gpx4 expression. Mechanistically, MALAT1 directly binds to miR-124-3p, which targets LPCAT3. miR-124-3p mimics abolished the protective effects of MALAT1, while LPCAT3 overexpression reversed the inhibitory effects of miR-124-3p mimics on cell viability and ferroptosis markers. In vivo, Dex reduced growth plate thickness, tibial length, and body weight gain, while both MALAT1 overexpression and 5-Aza treatment attenuated these deficits and restored LPCAT3 expression. In conclusion, DNA methylation-mediated MALAT1 downregulation promotes Dex-induced chondrocyte ferroptosis via the miR-124-3p/LPCAT3 axis. Targeting this pathway may represent a preclinically promising therapeutic strategy that warrants further investigation in glucocorticoid-induced growth retardation in children.