M6a-Driven Autophagy Impairs Osteogenesis In Diabetic Osteoporosis Via Akt2

To investigate how m6A-mediated autophagy via PI3K/AKT2/mTOR pathway compromises osteogenic potential of adipose-derived stem cells (ASCs) in diabetic osteoporosis (DOP), addressing a critical gap in regenerative strategies for metabolic bone disorders (reference: Peng S, et al. m6A modulates bone homeostasis. Cell Stem Cell 2023;32:123-135). DOP was induced in male C57BL/6 mice (n=30/group) by high-fat diet/STZ injection (ethics approved). ASCs were isolated from DOP/control mice. m6A-modified autophagy-related mRNAs were screened via RNA-seq/m6A-chip. Functional validation employed lentiviral AKT2 silencing/overexpression, MeRIP-qPCR, and osteogenic assays (ALP/ARS staining, WB, mRFP-GFP-LC3B autophagy flux). DOP-ASCs showed hypomethylated AKT2 (Chr7:2427 site), activating PI3K/AKT2/mTOR and suppressing autophagy (↓LC3-II, ↑SQSTM1) and osteogenesis (↓RUNX2/OPN). AKT2 knockdown rescued autophagic flux and mineralization, while overexpression replicated DOP phenotypes. First evidence that m6A hypomethylation of AKT2 drives DOP-associated osteogenic failure via autophagy dysregulation, offering a novel epigenetic target for bone regeneration in diabetes. Aligns with FDI’s focus on innovative translational solutions for oral-systemic health.