Researchers identify a shared SIRT1–FOXO3–DEPP1 signaling axis linking osteoporosis and depression after menopause
Postmenopausal women are at higher risk for both osteoporosis and depression, yet no single treatment effectively addresses both conditions because their shared biological basis remains poorly understood. In a recent study, researchers discovered that a traditional plant extract used in traditional Chinese medicine could act on a common molecular pathway underlying both bone loss and mood disorders, paving the way for treatments that target both conditions at once.
For many women, menopause brings more than just hormonal changes. Postmenopausal women often face two seemingly unrelated health challenges at once: osteoporosis and depression. These conditions tend to co-occur because they are both linked to estrogen levels. Specifically, estrogen loss increases oxidative stress—a state in which highly reactive molecules accumulate and damage cells—and impairs mitochondria, the organelles that power cells. These disruptions not only harm bone-forming cells, but also affect the brain’s mood-regulating regions.
Despite the overlap between these conditions, modern medicine still treats them separately. Simply put, drugs for osteoporosis can strengthen bones but do little for mood, and antidepressants do not prevent bone loss. While hormone replacement therapy can address both, its long-term use increases the risks of cardiovascular disease and certain estrogen-related cancers, making it unsuitable for many women. The deeper problem is that scientists have struggled to pinpoint a shared molecular mechanism linking bone and brain health in postmenopausal women.
Recently, a research team led by Dr. Xu Wei, Dr. Kai Sun (China Academy of Chinese Medical Sciences), Professor Weiwei Tao (Nanjing University of Chinese Medicine), and Dr. Zhiwen Luo (Fudan University) sought to address this knowledge gap. Their work, examined whether a well-known plant extract could act on a common biological pathway affecting both bone and brain.
The plant extract in question was total flavonoids from
Drynaria fortunei (TFDF), used widely in traditional Chinese medicine for its regenerative and strengthening effects on bone. The research team sought to test its impact in an animal model designed to mimic both postmenopausal osteoporosis and depression at the same time. To do this, the researchers used mice that had undergone ovary removal (to mimic menopause) and chronic stress exposure (to induce depression-like behavior). In this way, they could study bone deterioration and behavioral changes together. The team carried out detailed molecular analyses in the animals’ bone tissue and the hippocampus, a brain region critical for mood regulation and stress response, alongside experiments in cultured bone cells and neurons.
The results were remarkably consistent across these systems, as TFDF improved bone density and restored the fine internal structure of bone while also reducing behaviors associated with depression, such as loss of interest in rewarding stimuli. Mice treated with TFDF also showed better-preserved neurons in the hippocampus. Moreover, at the cellular level, TFDF helped restore mitochondrial function and autophagy, which is a process cells use to recycle damaged components.
Central to these effects was a signaling pathway involving three key molecules: SIRT1, FOXO3, and DEPP1. SIRT1 is a protein that helps cells respond to stress and maintain proper energy balance. The study revealed that TFDF activated SIRT1, which in turn restored the function of FOXO3. This then reduced the levels of DEPP1, a stress-responsive protein involved in autophagy regulation and cellular damage under oxidative conditions. This cascade is what ultimately helped normalize both mitochondrial function and cell recycling in bone and brain cells. “
To our knowledge, this is the first study to investigate TFDF in an integrated comorbidity model, enabling the simultaneous assessment of skeletal and neural outcomes within one framework,” highlights Dr. Wei Xu Most importantly, this integrated approach enabled the researchers to identify a shared biological pathway underlying both conditions, rather than studying them in isolation.
Overall, the findings suggest a new way of thinking about postmenopausal health. Instead of treating bone loss and depression as separate diseases, they may partly reflect different outcomes of a shared cellular stress response. Thus, by targeting that shared mechanism, it may be possible to treat both conditions at once. “
Our results suggest that TFDF may offer a practical ‘single agent, dual organ’ strategy for treating postmenopausal osteoporosis with depression, which merits further comparative evaluation with other SIRT1 activators and autophagy modulators,” adds Dr. Wei Xu.
If these findings hold up in future human studies, they could help inform new treatment approaches to simultaneously address bone and brain health in postmenopausal women with a single plant extract.
Keywords
Health, Medicine, Menopause, Osteoporosis, Depression
The complete study is accessible via DOI:10.34133/research.1125
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Launched in 2018,
Research is the first journal in the Science Partner Journal (SPJ) program.
Research is published by the American Association for the Advancement of Science (AAAS) in association with Science and Technology Review Publishing House.
Research publishes fundamental research in the life and physical sciences as well as important findings or issues in engineering and applied science. The journal publishes original research articles, reviews, perspectives, and editorials. IF=10.7, Citescore=13.3
Funding information
The study was supported by the National Natural Science Foundation of China (grant nos. 82575111 and 82205140), the Basic Research Program of Jiangsu Province (Natural Science Foundation; grant no. BK20220468), and the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences (No. CI2024D003).