Jin Jiahao, Yuan Zihao, Wang Xinglang, Li Quanfeng, Zhang Yunhui, Zhang Yibin, Ji Pengfei, Wu Yanfeng, Wang Peng, Liu Wenjie
Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, China.
Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, China.
Biomedicines. 2025 Apr 11;13(4):940. doi: 10.3390/biomedicines13040940.
: The imbalance between the osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs) is a key factor in the progression of osteoporosis; therefore, it is crucial to study the regulatory mechanisms that maintain this balance. Ferroptosis is a form of regulated cell death caused by the accumulation of lipid peroxides and is closely associated with various diseases. Changes in intracellular oxidative stress levels can affect the lineage allocation of MSCs. However, it remains unclear whether the disruption of intracellular oxidative stress levels caused by ferroptosis can influence the osteogenic-adipogenic differentiation balance of MSCs, and the mechanism underlying this influence in osteoporosis has not been fully elucidated. This study is the first to demonstrate through in vitro cell experiments that inhibiting ferroptosis can decrease the adipogenic differentiation of MSCs. Through bioinformatics analysis, differentially expressed genes (DEGs) associated with the adipogenic differentiation of MSCs were identified from the GEO database. We then intersected these differentially expressed genes with a ferroptosis-related gene dataset and identified 118 ferroptosis-related differentially expressed genes (FRDEGs). Additionally, we explored the functional roles of FRDEGs through GO and KEGG analyses and found that these genes significantly impacted intracellular oxidative stress. Furthermore, we identified 10 key FRDEGs via protein-protein interaction (PPI) analysis. The diagnostic performance of these genes was evaluated by plotting receiver operating characteristic (ROC) curves, and the reliability of the diagmodel was validated using data from osteoporosis patients. We then constructed a mouse osteoporosis model and validated the mRNA expression levels of key FRDEGs via qRT-PCR, which revealed significant differences in expression in the osteoporosis group. Finally, molecular docking technology was used to identify two small molecules from the DrugBank database that are able to negatively regulate MSC adipogenic differentiation by inhibiting ferroptosis. The identified FRDEGs and small molecules offer novel diagnostic markers and therapeutic candidates for osteoporosis.
间充质干细胞（MSCs）成骨与成脂分化之间的失衡是骨质疏松症进展的关键因素；因此，研究维持这种平衡的调控机制至关重要。铁死亡是一种由脂质过氧化物积累引起的程序性细胞死亡形式，与多种疾病密切相关。细胞内氧化应激水平的变化会影响MSCs的谱系分配。然而，铁死亡引起的细胞内氧化应激水平破坏是否会影响MSCs的成骨-成脂分化平衡，以及这种影响在骨质疏松症中的潜在机制尚未完全阐明。本研究首次通过体外细胞实验证明，抑制铁死亡可减少MSCs的成脂分化。通过生物信息学分析，从GEO数据库中鉴定出与MSCs成脂分化相关的差异表达基因（DEGs）。然后，我们将这些差异表达基因与铁死亡相关基因数据集进行交叉分析，鉴定出118个铁死亡相关差异表达基因（FRDEGs）。此外，我们通过基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析探索了FRDEGs的功能作用，发现这些基因显著影响细胞内氧化应激。此外，我们通过蛋白质-蛋白质相互作用（PPI）分析确定了10个关键的FRDEGs。通过绘制受试者工作特征（ROC）曲线评估这些基因的诊断性能，并使用骨质疏松症患者的数据验证诊断模型的可靠性。然后，我们构建了小鼠骨质疏松症模型，并通过qRT-PCR验证了关键FRDEGs的mRNA表达水平，结果显示骨质疏松症组的表达存在显著差异。最后，利用分子对接技术从DrugBank数据库中鉴定出两种能够通过抑制铁死亡来负调控MSCs成脂分化的小分子。所鉴定的FRDEGs和小分子为骨质疏松症提供了新的诊断标志物和治疗候选物。
