m⁶A-modified DRAM1 recognized by YTHDF1 regulates autophagy during dexamethasone-induced osteogenic inhibition

Bone health is critically dependent on the precise regulation of bone-forming cells, which are significantly impacted by glucocorticoids. Although DNA damage-regulated autophagy modulator 1 (DRAM1) plays a key role in autophagy, its involvement in glucocorticoid-induced osteoporosis has not been fully explored. Here, we showed that alterations in N⁶-methyladenosine (m⁶A) levels contributed to the regulation of DRAM1 under dexamethasone treatment. In vitro, our research revealed that high doses of dexamethasone impaired the m⁶A-dependent regulation of DRAM1 by YTH m⁶A RNA binding protein F1 (YTHDF1), leading to decreased DRAM1 levels and subsequent disruption of autophagy-associated osteogenic differentiation in human bone marrow mesenchymal stem cells (hBMSCs) and MC3T3-E1 cells. Additionally, the classic Wnt/β-catenin pathway, which plays a critical role in bone formation, was shown to be modulated by DRAM1 during osteogenic differentiation. In vivo experiments showed that DRAM1 protein expression in the femurs of Ythdf1 knockout (KO) mice was significantly lower than that in the wild-type (WT) group, and that resveratrol not only mitigated dexamethasone-induced bone damage but was also associated with increased DRAM1 expression. These findings advance our understanding of how glucocorticoids hinder bone formation and suggest that targeting the m⁶A-dependent YTHDF1/DRAM1 regulatory axis may offer novel strategies for osteoporosis treatment.