ALDH2/eIF3E Interaction Modulates Protein Translation Critical for Cardiomyocyte Ferroptosis in Acute Myocardial Ischemia Injury

Xin Chen^#¹, Xiujian Yu^#², Shanshan Zhong^#³, Ping Sha², Rui Li^{1

4}, Xiaodong Xu¹, Ningning Liang¹, Lili Zhang¹, Luxiao Li¹, Jingyu Zhang⁵, Mingyao Zhou⁵, Tongwei Lv⁵, Haoran Ma¹, Yongqiang Wang^{1

6}, Yanwen Ye⁷, Chunzhao Yin^{1

4}, Shiting Chen¹, Jinwei Tian⁸, Aijun Sun^{9

10}, Weiyuan Wang¹¹, Dewen Yan¹¹, Huangtian Yang^{2

3

4}, Hui Huang¹², Pan Li⁵, Huiyong Yin¹

Affiliations

¹ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China (X.C., R.L., X.X., N.L., L.Z., L.L., H.M., Y.W., C.Y., S.C., H.Y.).
² CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Shanghai, China (X.Y., P.S., H.Y.).
³ Department of Biomedical Sciences, College of Biomedicine, Institute of Digital Medicine, Tung Biomedical Science Center, State Key Laboratory of Marine Environmental Health (SKLMEH), The Shenzhen Research Institute and Futian Research Institute, City University of Hong Kong, Hong Kong, China (S.Z., H.Y.).
⁴ School of Life Science and Technology, ShanghaiTech University, Shanghai, China (R.L., C.Y., H.Y.).
⁵ Department of Cardiology, Naval Medical University, Shanghai, China (J.Z., M.Z., T.L., P.L.).
⁶ Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan, China (Y.W.).
⁷ Bio-med Big Data Center, CAS Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Shanghai, China (Y.Y.).
⁸ Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China (J.T.).
⁹ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (A.S.).
¹⁰ Institutes of Biomedical Sciences, Fudan University, Shanghai, China (A.S.).
¹¹ Department of Endocrinology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen Clinical Research Center for Metabolic Diseases, Shenzhen Center for Diabetes Control and Prevention, Shenzhen, Guangdong Province, China (W.W., D.Y.).
¹² Department of Cardiology, The Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China (H.H.).

^# Contributed equally.

PMID: 41111418
DOI: 10.1161/CIRCULATIONAHA.125.075220

Free article

ALDH2/eIF3E Interaction Modulates Protein Translation Critical for Cardiomyocyte Ferroptosis in Acute Myocardial Ischemia Injury

Xin Chen et al. Circulation. 2025.

Free article

. 2025 Oct 20.

doi: 10.1161/CIRCULATIONAHA.125.075220. Online ahead of print.

Authors

Affiliations

¹ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China (X.C., R.L., X.X., N.L., L.Z., L.L., H.M., Y.W., C.Y., S.C., H.Y.).
² CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Shanghai, China (X.Y., P.S., H.Y.).
³ Department of Biomedical Sciences, College of Biomedicine, Institute of Digital Medicine, Tung Biomedical Science Center, State Key Laboratory of Marine Environmental Health (SKLMEH), The Shenzhen Research Institute and Futian Research Institute, City University of Hong Kong, Hong Kong, China (S.Z., H.Y.).
⁴ School of Life Science and Technology, ShanghaiTech University, Shanghai, China (R.L., C.Y., H.Y.).
⁵ Department of Cardiology, Naval Medical University, Shanghai, China (J.Z., M.Z., T.L., P.L.).
⁶ Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan, China (Y.W.).
⁷ Bio-med Big Data Center, CAS Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Shanghai, China (Y.Y.).
⁸ Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China (J.T.).
⁹ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China (A.S.).
¹⁰ Institutes of Biomedical Sciences, Fudan University, Shanghai, China (A.S.).
¹¹ Department of Endocrinology, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen Clinical Research Center for Metabolic Diseases, Shenzhen Center for Diabetes Control and Prevention, Shenzhen, Guangdong Province, China (W.W., D.Y.).
¹² Department of Cardiology, The Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China (H.H.).

^# Contributed equally.

PMID: 41111418
DOI: 10.1161/CIRCULATIONAHA.125.075220

Abstract

Background: As an iron-dependent form of regulated cell death caused by lipid peroxidation, ferroptosis has been implicated in ischemic injury, but the underlying mechanisms in acute myocardial infarction (AMI) remain poorly defined. ALDH2 (acetaldehyde dehydrogenase 2) catalyzes detoxification of lipid aldehydes derived from lipid peroxidation and acetaldehydes from alcohol consumption. The Glu504Lys polymorphism of ALDH2 (rs671, ALDH2*2), affecting ≈40% of East Asians, is associated with increased risk of myocardial infarction (MI). This study aims to investigate the role of ALDH2*2 and ferroptosis in AMI.

Methods: A Chinese cohort of 177 patients with acute heart failure with ALDH2 wild type and ALDH2*2 was enrolled. The MI mouse model of left anterior descending coronary artery ligation was conducted on wild-type and ALDH2*2 mice and mice with cardiomyocyte-specific knockdown of eIF3E (eukaryotic translation initiation factor 3 subunit E) by adeno-associated virus. The lipid peroxidation products were measured by mass spectrometry-based lipidomics and metabolomics in human plasma, mouse serum samples, mouse heart tissues, and primary cardiac myocytes.

Results: Human ALDH2*2 carriers exhibit more severe heart failure after AMI with features of ferroptosis in plasma, as seen through lipidomic analysis, characterized by increased bioactive lipids and decreased antioxidants, such as coenzyme Q10 and BH4 (tetrahydrobiopterin). Similar features were observed in MI mouse models of ALDH2*2, whereas ferroptosis inhibition by Fer-1 significantly improved heart function and reversed ferroptosis markers. Importantly, ALDH2*2 significantly decreased ALDH2 protein levels, whereas ferroptosis-related markers, including TFRC (transferrin receptor) and ACSL4 (acyl-coenzyme A synthetase long-chain family member 4) were notably upregulated in the infarct heart tissues. Mechanistically, ALDH2 physically interacts with the eIF3 complex via the eIF3E factor, which prevents eIF3E-eIF4G1 (eukaryotic initiation factor 4G)-mRNA assembly. The ALDH2*2 variant causes ALDH2 deficiency, disrupting its interaction with the eIF3 complex by releasing the bound eIF3E to assemble an eIF3E-eIF4G1-mRNA ternary complex, thereby driving selective translation of mRNAs (eg, TFRC, ACSL4, and UAP1) containing the GAGGACR (R represents A/G) motif to promote ferroptosis. Consistently, cardiomyocyte-specific eIF3E knockdown restored ALDH2*2 cardiac function by attenuating ferroptosis in MI.

Conclusions: ALDH2*2 aggravates acute heart failure after MI by promoting the selective translation of mRNAs containing the GAGGACR motif, thereby driving cardiomyocyte ferroptosis. Targeting ferroptosis represents a potential therapeutic option for mitigating MI injury, especially for ALDH2*2 carriers.

Keywords: ALDH2; eIF3E; ferroptosis; myocardial infarction; protein translation.

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ALDH2/eIF3E Interaction Modulates Protein Translation Critical for Cardiomyocyte Ferroptosis in Acute Myocardial Ischemia Injury

Affiliations

ALDH2/eIF3E Interaction Modulates Protein Translation Critical for Cardiomyocyte Ferroptosis in Acute Myocardial Ischemia Injury

Authors

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Abstract

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Full Text Sources

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