Cardiomyocyte PIK3R1 deficiency attenuates mitochondrial dynamic imbalance and ferroptosis in diabetic cardiomyopathy in association with the PI3K/Akt/Nrf2 axis
5 affiliations
- 1Department of Clinical Pharmacy, Shaoxing TCM Hospital Affiliated to Zhejiang Chinese Medical University, Shaoxing, China
- 2Department of Clinical Pharmacy, The People’s Hospital of Pingyang, Wenzhou, China
- 3Department of Clinical Pharmacy, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- 4Department of Pharmacy, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- 5Department of Medicine Pharmacy, Shaoxing TCM Hospital Affiliated to Zhejiang Chinese Medical University, Shaoxing, China
Abstract
Objective: PIK3R1 encodes the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K) and negatively regulates PI3K signaling. Our prior study identified abnormal PIK3R1 expression in diabetic cardiomyopathy (DCM), but its role and underlying mechanisms in DCM pathogenesis remain unclear. This study aimed to elucidate the functional significance of PIK3R1 and its molecular mechanism in regulating mitochondrial homeostasis, cardiomyocyte ferroptosis, and DCM progression.
Methods: A DCM mouse model was established by high-fat diet (HFD) feeding combined with low-dose streptozotocin (STZ) injection. Cardiomyocyte-specific PIK3R1 knockout (PIK3R1KO) mice were generated using the Cre-LoxP system. Five in vivo cohorts were studied: control and DCM mice; DCM mice treated with the ferroptosis inhibitor ferrostatin-1; DCM mice treated with the mitochondrial fission inhibitor Mdivi-1; wild-type and PIK3R1KO mice with or without the PI3K/Akt agonist 740 Y-P; and PIK3R1KO DCM mice receiving AAV9-Drp1 or AAV9 vector. Cardiac function was evaluated by echocardiography. Mitochondrial morphology and function were assessed by transmission electron microscopy, myocardial ATP content, mitochondrial DNA copy number and reactive oxygen species (ROS) detection. Cardiomyocyte ferroptosis was determined by iron content measurement, lipid peroxidation assay, and expression analysis of ferroptosis-related markers (GPX4, ACSL4, SLC7A11). The PI3K/Akt/Nrf2 signaling pathway was examined using Western blot and immunofluorescence staining.
Results: DCM mice exhibited impaired cardiac function (decreased left ventricular ejection fraction and fractional shortening), myocardial apoptosis, mitochondrial dysfunction (fragmentation, reduced ATP content, increased ROS production), and enhanced ferroptosis (elevated iron deposition, lipid peroxidation, downregulated GPX4 and SLC7A11, upregulated ACSL4). Treatment with the mitochondrial division inhibitor Mdivi-1 improved mitochondrial homeostasis, inhibited ferroptosis, and attenuated DCM progression. PIK3R1 deficiency in DCM mice significantly ameliorated mitochondrial dynamic imbalance, suppressed cardiomyocyte ferroptosis, and rescued cardiac function by activating the PI3K/Akt/Nrf2 pathway. However, Drp1 overexpression reversed the protective effects of PIK3R1 knockout on mitochondrial function and ferroptosis in DCM mice.
Conclusion: Cardiomyocyte PIK3R1 deficiency is associated with preserved mitochondrial dynamic homeostasis, reduced cardiomyocyte ferroptosis and attenuated DCM progression, together with increased PI3K/Akt/Nrf2 signalling. Whether this pathway mediates the effect requires direct loss-of-function testing, and PIK3R1 may warrant evaluation as a candidate therapeutic target for DCM.
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BibTeX
@article{zhou2026cardiomyocyte,
title = {{Cardiomyocyte PIK3R1 deficiency attenuates mitochondrial dynamic imbalance and ferroptosis in diabetic cardiomyopathy in association with the PI3K/Akt/Nrf2 axis}},
author = {Jiefang Zhou and Qianqian Xiao and Fangfang Zhang and Xiuwei Shen and Shujuan Wu and Linling Wang and Chunyan Huang},
journal = {Frontiers in Cell and Developmental Biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1953037},
url = {https://doi.org/10.3389/fcell.2026.1953037},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cardiomyocyte PIK3R1 deficiency attenuates mitochondrial dynamic imbalance and ferroptosis in diabetic cardiomyopathy in association with the PI3K/Akt/Nrf2 axis
AU - Jiefang Zhou
AU - Qianqian Xiao
AU - Fangfang Zhang
AU - Xiuwei Shen
AU - Shujuan Wu
AU - Linling Wang
AU - Chunyan Huang
PY - 2026
DA - 2026/10/21
JO - Frontiers in Cell and Developmental Biology
DO - 10.3389/fcell.2026.1953037
UR - https://doi.org/10.3389/fcell.2026.1953037
AB - Objective: PIK3R1 encodes the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K) and negatively regulates PI3K signaling. Our prior study identified abnormal PIK3R1 expression in diabetic cardiomyopathy (DCM), but its role and underlying mechanisms in DCM pathogenesis remain unclear. This study aimed to elucidate the functional significance of PIK3R1 and its molecular mechanism in regulating mitochondrial homeostasis, cardiomyocyte ferroptosis, and DCM progression. Methods: A DCM mouse model was established by high-fat diet (HFD) feeding combined with low-dose streptozotocin (STZ) injection. Cardiomyocyte-specific PIK3R1 knockout (PIK3R1KO) mice were generated using the Cre-LoxP system. Five in vivo cohorts were studied: control and DCM mice; DCM mice treated with the ferroptosis inhibitor ferrostatin-1; DCM mice treated with the mitochondrial fission inhibitor Mdivi-1; wild-type and PIK3R1KO mice with or without the PI3K/Akt agonist 740 Y-P; and PIK3R1KO DCM mice receiving AAV9-Drp1 or AAV9 vector. Cardiac function was evaluated by echocardiography. Mitochondrial morphology and function were assessed by transmission electron microscopy, myocardial ATP content, mitochondrial DNA copy number and reactive oxygen species (ROS) detection. Cardiomyocyte ferroptosis was determined by iron content measurement, lipid peroxidation assay, and expression analysis of ferroptosis-related markers (GPX4, ACSL4, SLC7A11). The PI3K/Akt/Nrf2 signaling pathway was examined using Western blot and immunofluorescence staining. Results: DCM mice exhibited impaired cardiac function (decreased left ventricular ejection fraction and fractional shortening), myocardial apoptosis, mitochondrial dysfunction (fragmentation, reduced ATP content, increased ROS production), and enhanced ferroptosis (elevated iron deposition, lipid peroxidation, downregulated GPX4 and SLC7A11, upregulated ACSL4). Treatment with the mitochondrial division inhibitor Mdivi-1 improved mitochondrial homeostasis, inhibited ferroptosis, and attenuated DCM progression. PIK3R1 deficiency in DCM mice significantly ameliorated mitochondrial dynamic imbalance, suppressed cardiomyocyte ferroptosis, and rescued cardiac function by activating the PI3K/Akt/Nrf2 pathway. However, Drp1 overexpression reversed the protective effects of PIK3R1 knockout on mitochondrial function and ferroptosis in DCM mice. Conclusion: Cardiomyocyte PIK3R1 deficiency is associated with preserved mitochondrial dynamic homeostasis, reduced cardiomyocyte ferroptosis and attenuated DCM progression, together with increased PI3K/Akt/Nrf2 signalling. Whether this pathway mediates the effect requires direct loss-of-function testing, and PIK3R1 may warrant evaluation as a candidate therapeutic target for DCM.
SN - 2296-634X
ER -