ArticleJournal of orthopaedic surgery and research2024
FNDC5/irisin ameliorates bone loss of type 1 diabetes by suppressing endoplasmic reticulum stress‑mediated ferroptosis.
Article in Journal of orthopaedic surgery and research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers, 2 of them syntheses that pooled it.
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10 citing papers in PubMed, 2 syntheses or guidelines pooled it, 15 citations in OpenAlex.
- The role of ferroptosis in osteoporosis: a cellular perspective on osteoblast, osteoclast and osteocyte dysfunction.Frontiers in endocrinology · 2026Pooled it
- Protective role of irisin on bone in osteoporosis: a systematic review of rodent studies.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2025Pooled it
- The Role of Ferroptosis in Diabetes Pathogenesis: Therapeutic Implications of Hydrogen Sulfide and Its Reactive Metabolites.Antioxidants (Basel, Switzerland) · 2026Review
- Exercise-Induced Irisin: A Novel Strategy for Neuroinflammation Alleviation and Neurorepair in Diabetic Retinopathy.International journal of molecular sciences · 2026Review
- Ferroptosis: unveiling a transformative perspective in the landscape of autoimmune diseases.Frontiers in immunology · 2026Review
- Ferroptosis in diabetes mellitus and its complications: overview of clinical and preclinical research.Cell death discovery · 2025Review
- Recent Updates on Diabetes and Bone.International journal of molecular sciences · 2025Review
- Iron dysregulation, ferroptosis, and oxidative stress in diabetic osteoporosis: Mechanisms, bone metabolism disruption, and therapeutic strategies.World journal of diabetes · 2025Review
- Role and Functions of Irisin: A Perspective on Recent Developments and Neurodegenerative Diseases.Antioxidants (Basel, Switzerland) · 2025Review
- Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects.Bone research · 2025Review
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundFerroptosis is known to play a crucial role in diabetic osteopathy. However, key genes and molecular mechanisms remain largely unclear. This study aimed to identify a crucial ferroptosis-related differentially expressed gene (FR-DEG) in diabetic osteopathy and investigate its potential mechanism.
methodsWe identified fibronectin type III domain-containing protein 5 (FNDC5)/irisin as an essential FR-DEG in diabetic osteopathy using the Ferroptosis Database (FerrDb) and GSE189112 dataset. Initially, a diabetic mouse model was induced by intraperitoneal injection of streptozotocin (STZ), followed by intraperitoneal injection of irisin. MC3T3-E1 cells treated with high glucose (HG) were used as an in vitro model. FNDC5 overexpression plasmid was used to explore underlying mechanisms in vitro experiments. Femurs were collected for micro-CT scan, histomorphometry, and immunohistochemical analysis. Peripheral serum was collected for ELISA analysis. Cell viability was assessed using a CCK-8 kit. The levels of glutathione (GSH), malondialdehyde (MDA), iron, reactive oxygen species (ROS), and lipid ROS were detected by the corresponding kits. Mitochondria ultrastructure was observed through transmission electron microscopy (TEM). Finally, mRNA and protein expressions were examined by quantitative real-time PCR (qRT-PCR) and western blot analysis.
resultsThe expression of FNDC5 was found to be significantly decreased in both in vivo and in vitro models. Treatment with irisin significantly suppressed ferroptosis and improved bone loss. This was demonstrated by reduced lipid peroxidation and iron overload, increased antioxidant capability, as well as the inhibition of the ferroptosis pathway in bone tissues. Furthermore, in vitro studies demonstrated that FNDC5 overexpression significantly improved HG-induced ferroptosis and promoted osteogenesis. Mechanistic investigations revealed that FNDC5 overexpression mitigated ferroptosis in osteoblasts by inhibiting the eukaryotic initiation factor 2 alpha (eIF2α)/activated transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) pathway.
conclusionsCollectively, our study uncovered the important role of FNDC5/irisin in regulating ferroptosis of diabetic osteopathy, which might be a potential therapeutic target.
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