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  3. GIPC1 governed ferroptosis by regulating DECR1-modulating lipid homeostasis during dilated cardiomyopathy (DCM)

GIPC1 governed ferroptosis by regulating DECR1-modulating lipid homeostasis during dilated cardiomyopathy (DCM)

  • Cell Death Differ. 2026 Mar 5. doi: 10.1038/s41418-026-01679-9.
Nannan Tang # 1,  Ruxue Mu # 1,  He Wang # 1,  Jiaying Wu # 1,  Jie Zhang 1,  Di Huang 2,  Yannan Han 1,  Wenjian Li 3,  Yuqing Chen 1,  Xiang Li 1,  Yilin Sun 1,  Zifeng Zhang 1,  Jinlu Zuo 1,  Ying Hu 1,  Yanan Yin 1,  Yang Qu 1,  Jinping Liu 4,  Lei Jiao 1,  Xue Liu 1,  Haihai Liang 1,  Ning Wang 1,  Yunlong Bai 1 5,  Yan Liu 6,  Bin Wang 7,  Dan Zhao 8,  Yu Liu 9,  Baofeng Yang 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Heilongjiang, 150081, China.
  • 2 Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Heilongjiang, 150081, China.
  • 3 Research Center for Pharmacoinformatics, College of Pharmacy, Harbin Medical University, Heilongjiang, 150081, China.
  • 4 Department of Cardiovascular Ultrasound, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
  • 5 Key Laboratory of Chronic disease Prevention and Control of Traditional Chinese Medicine of Guangdong Higher Education Institutes, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
  • 6 College of Pharmacy, Hainan Medical University, Haikou, 571199, China.
  • 7 Department of Cardiovascular Ultrasound, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China. [email protected].
  • 8 Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Heilongjiang, 150081, China. [email protected].
  • 9 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Heilongjiang, 150081, China. [email protected].
  • 10 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Heilongjiang, 150081, China. [email protected].
  • # Contributed equally.
PMID: 41787053 DOI: 10.1038/s41418-026-01679-9
Abstract

Dilated cardiomyopathy (DCM) was the most prevalent cardiomyopathy worldwide. Although Ferroptosis has been implicated in cardiac pathogenesis, its regulatory mechanism in DCM remained poorly defined. In this study, we found that GIPC1 (GAIP/RGS19-interacting protein), a scaffolding protein, was significantly downregulated in cardiac tissues from DCM patients and doxorubicin (DOX)-induced DCM models. Integrated proteomic and lipidomic analysis revealed that cardiac-specific knockout of GIPC1 disrupted mitochondrial fatty acid metabolism, increased the abundance of polyunsaturated fatty acid-containing Phospholipids (PUFA-PLs), and ultimately promoted Ferroptosis in cardiomyocytes. Both in vitro and in vivo experiments demonstrated that GIPC1 deficiency exacerbated Ferroptosis and cardiac dysfunction in DOX-induced cardiomyopathy, whereas GIPC1 overexpression conferred protection against Ferroptosis in DOX-induced cardiomyopathy. Mechanistically, co-immunoprecipitation mass spectrometry (Co-IP/MS) and molecular docking demonstrated that GIPC1 interacted with mitochondrial 2,4-dienoyl-CoA reductase (DECR1) via its PDZ domain. Surface plasmon resonance (SPR) analysis further confirmed a high-affinity direct binding between GIPC1 and DECR1 (KD = 16.3 nM). Co-IP and immunofluorescence (IF) demonstrated that GIPC1 facilitated actin-dependent transport of DECR1 into mitochondria, thereby maintaining redox homeostasis and suppressing Ferroptosis. Consistently, DECR1 overexpression rescued GIPC1 ablation-induced Ferroptosis by balancing redox homeostasis. Together, these results demonstrated that GIPC1 reduced cardiomyocyte susceptibility to Ferroptosis by promoting mitochondrial translocation of DECR1 and remodeling lipid homeostasis, highlighting GIPC1/DECR1 axis as a potential therapeutic strategy for DCM. A schematic model illustrating the pathogenic cascade triggered by GIPC1 deficiency during DCM. In DCM, the expression level of GIPC1 was downregulated, thereby inhibiting actin-dependent transport of DECR1 into mitochondria, which remodeled lipid homeostasis and ultimately induced cardiomyocytes Ferroptosis. Created with Figdraw.com.

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