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Fibroblast growth factor 21 improves diabetic cardiomyopathy by inhibiting ferroptosis via ferritin pathway
Ruxin Wang1,2, Xiaofang Zhang3, Haowen Ye1
1Department of Endocrinology and Metabolism, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China.
Insights
Fibroblast growth factor 21 (FGF21) protects against diabetic cardiomyopathy (DCM) by inhibiting ferroptosis. This study reveals the ATF4-FGF21-ferritin pathway as a novel therapeutic target for DCM.
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Research
- Cellular Mechanisms of Disease
Background:
- Diabetic cardiomyopathy (DCM) is a severe complication of type 2 diabetes mellitus with complex, poorly understood mechanisms.
- Ferroptosis, a form of regulated cell death, is implicated in cardiovascular disease but less studied in DCM.
- Fibroblast growth factor 21 (FGF21) is linked to ferroptosis and shows potential in treating metabolic and cardiovascular diseases.
Purpose of the Study:
- To confirm ferroptosis's role in DCM.
- To investigate if FGF21 mitigates DCM by inhibiting ferroptosis.
- To elucidate the specific molecular mechanisms underlying FGF21's effects in DCM.
Main Methods:
- Established animal DCM models using high-fat diet/streptozotocin or db/db mice.
- Created a diabetic cardiomyocyte injury model with high glucose/high fat (HG/HF) culture.
- Utilized adeno-associated virus 9-FGF21, FGF21 siRNA, and overexpression plasmids for FGF21 intervention.
Main Results:
- Ferroptosis was significantly exacerbated in DCM models.
- FGF21 overexpression improved cardiac function and reduced ferroptosis; FGF21 knockdown worsened these outcomes.
- FGF21 directly stabilized ferritin by reducing its degradation, thereby inhibiting ferroptosis.
- Activating transcription factor 4 (ATF4) was identified as an upstream regulator of FGF21.
Conclusions:
- The ATF4-FGF21-ferritin axis plays a crucial role in protecting against DCM via ferroptosis.
- This pathway represents a promising therapeutic target for managing diabetic cardiomyopathy.
Background:
Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 2 diabetes mellitus, and its mechanisms are complex and poorly understood. Despite growing evidence suggesting that ferroptosis plays a significant role in cardiovascular disease, it has been less extensively studied in DCM. Fibroblast growth factor 21 (FGF21), whose mechanism of action is closely related to ferroptosis, is widely utilized in studies focused on the prevention and treatment of glucolipid metabolism-related diseases and cardiovascular diseases.
Objective:
To confirm the significant role of ferroptosis in DCM and to investigate whether FGF21 improves DCM by inhibiting ferroptosis and elucidating its specific molecular mechanisms.
Methods:
The animal DCM models were established through high-fat feeding combined with streptozotocin injection in C57BL/6J mice or by db/db mice, and the diabetic cardiomyocyte injury model was created using high glucose and high fat (HG/HF) culture of primary cardiomyocytes. Intervention modeling of FGF21 were performed by injecting adeno-associated virus 9-FGF21 in mice and transfecting FGF21 siRNA or overexpression plasmid in primary cardiomyocytes.
Results:
The findings indicated that ferroptosis was exacerbated and played a significant role in DCM. The overexpression of FGF21 inhibited ferroptosis and improved cardiac injury and function, whereas the knockdown of FGF21 aggravated ferroptosis and cardiac injury and function in DCM. Furthermore, we discovered that FGF21 inhibited ferroptosis in DCM by directly acting on ferritin and prolonging its half-life. Specifically, FGF21 binded to the heavy and light chains of ferritin, thereby reducing its excessive degradation in the proteasome and lysosomal-autophagy pathways in DCM. Additionally, activating transcription factor 4 (ATF4) served as the upstream regulator of FGF21 in DCM.
Conclusions:
The ATF4-FGF21-ferritin axis mediates the protective effects in DCM through the ferroptosis pathway and represents a potential therapeutic target for DCM.
