Targeting a Shared Mitophagy Regulator: The SIRT1–FOXO3–DEPP1 Axis Underpins the Dual Bone and Brain Benefits of Total Flavonoids from Drynaria fortunei

Postmenopausal osteoporosis and depression often occur together, but a single treatment that improves both conditions is currently lacking. The loss of estrogen can trigger oxidative stress, damage mitochondria, and drive dysregulated autophagy with impaired flux, simultaneously harming bone and the brain. We evaluated whether total flavonoids from Drynaria fortunei (TFDF) could counter these problems by activating sirtuin-1 (SIRT1), a protein that supports autophagy and mitochondrial health. In menopausal and chronic stress model mice and in cultured bone-forming cells and hippocampal neurons exposed to oxidative injury, we measured bone structure and strength indicators, mood-related behaviors, mitochondrial function, and gene activity patterns. The flavonoids preserved bone density and fine bone structure, shifted bone turnover toward formation, and improved depression-like behaviors (greater exploration and sucrose preference, less immobility). Across bone and the brain, TFDF modulated SIRT1–FOXO3–DEPP1 signaling and FOXO-linked oxidative stress and autophagy programs, thereby normalizing autophagic recycling and mitochondrial function. In cellular models, TFDF preserved mitochondrial function and restored autophagic recycling, and the loss or gain of SIRT1 function abolished or enhanced these benefits, respectively, indicating that SIRT1 activity is necessary for the effects of TFDF. These findings identify TFDF as a single, mechanism-based strategy that addresses both skeletal deterioration and depressive symptoms after menopause by engaging SIRT1-dependent stress autophagy pathways to restore cellular recycling and energy control.