山奈素通过METTL3/YTHDF2调控的PTEN mRNA甲基化及抑制铁蛋白自噬-铁死亡，减轻2型糖尿病性骨质疏松症

Abstract

Kaempferol mitigates bone loss and BMSC dysfunction in type 2 diabetic osteoporosis. • Kaempferol suppresses ferritinophagy-ferroptosis by activating the PI3K/AKT pathway. • Kaempferol enhances METTL3-mediated PTEN m⁶A methylation recognized by YTHDF2. • YTHDF2 inhibition abolishes the osteoprotective effects of kaempferol in T2DOP mice. Type 2 diabetic osteoporosis (T2DOP) features impaired bone quality and high fracture risk, with unclear pathogenesis and limited targeted therapies. This study explored the therapeutic effect and molecular mechanism of kaempferol against T2DOP via m⁶A modification and ferritinophagy-dependent ferroptosis using bioinformatic, cellular and animal approaches. We analyzed the single-cell RNA-seq dataset GSE212726, and predicted core targets of kaempferol through network pharmacology and molecular docking. A high-glucose-high-fat (HGHF)-induced T2DOP cellular model and streptozotocin plus high-fat diet-induced mouse T2DOP model were established for functional verification with multiple molecular assays and DC-Y13–27 (a selective YTHDF2 antagonist) rescue experiments. We found ferritinophagy and ferroptosis were highly activated in T2DOP-derived BMSCs. HGHF triggered ferroptosis, disrupted BMSC functions and osteogenic-adipogenic balance, which was rescued by kaempferol. Mechanistically, kaempferol elevates METTL3 expression to promote m⁶A modification of PTEN mRNA. Subsequent recognition of methylated PTEN by YTHDF2 accelerates PTEN degradation, which further activates PI3K/AKT signaling and ultimately suppresses ferritinophagy-triggered ferroptosis. In vivo, kaempferol alleviated bone microstructure deterioration in T2DOP mice, while DC-Y13–27 reversed these protective effects. In summary, kaempferol alleviates T2DOP by suppressing ferritinophagy-dependent ferroptosis via the METTL3/YTHDF2/PTEN/PI3K/AKT axis, offering a promising therapeutic candidate for T2DOP. Download: Download high-res image (156KB) Download: Download full-size