Multi-region proteomic mapping identifies FTL1 and SERPINA3K as protective factors in cardiac aging

  • Cell Death Dis. 2026 May 23;17(1):647. doi: 10.1038/s41419-026-08882-z.
Jingnan Huang  #  1  2  3 ,  Xin Sun  #  2  3 ,  Huadong Liu  #  2  3 ,  Kunpeng Li  4 ,  Xin Liu  1  3 ,  Yunmeng Bai  1  3 ,  Zhiyu Dong  1 ,  Xinlei Wu  5 ,  Xinyi Liu  5 ,  Lin Jia  5 ,  Jianlong Yan  2 ,  Lixin Cheng  1 ,  Jigang Wang  6  7  8 ,  Lingyun Dai  9  10  11 ,  Qingshan Geng  12
Affiliations
  • 1. Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Department of Geriatrics, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, 518020, China.
  • 2. Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, 518020, China.
  • 3. Department of Pharmacology, School of Medicine and SUSTech Homeostatic Medicine Institute (SHMI), Southern University of Science and Technology, Shenzhen, 518055, China.
  • 4. School of Software, Beihang University, Beijing, 100191, China.
  • 5. College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China.
  • 6. Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Department of Geriatrics, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, 518020, China. [email protected].
  • 7. Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, 518020, China. [email protected].
  • 8. Department of Pharmacology, School of Medicine and SUSTech Homeostatic Medicine Institute (SHMI), Southern University of Science and Technology, Shenzhen, 518055, China. [email protected].
  • 9. Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Department of Geriatrics, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, 518020, China. [email protected].
  • 10. Department of Pharmacology, School of Medicine and SUSTech Homeostatic Medicine Institute (SHMI), Southern University of Science and Technology, Shenzhen, 518055, China. [email protected].
  • 11. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore. [email protected].
  • 12. Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Department of Geriatrics, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University), Shenzhen, 518020, China. [email protected].
  • # Contributed equally.
PMID: 42177202 DOI: 10.1038/s41419-026-08882-z
Abstract

Aging is a well-recognized risk factor in cardiovascular diseases (CVDs), primarily due to its association with the gradual decline in cardiac function. This decline significantly influences the pathogenesis of common CVDs such as myocardial infarction and heart failure. Despite the existence of several proteomic atlases of the heart, the spatially resolved proteomic dynamics essential for understanding region-specific aging mechanisms in cardiac tissue remain incompletely characterized. In this study, we conducted a region-resolved quantitative proteomic profiling for various murine cardiac regions at three distinct stages of aging (3, 12, and 20-month-old), quantifying 6 650 proteins in the heart. Leveraging integrated bioinformatics and machine learning frameworks, we uncovered that FTL1 and SERPINA3K exhibit strong age-associated expression changes across all cardiac regions. Mechanistically, the knockdown of Ftl1 led to cardiomyocyte Ferroptosis and senescence, phenotypes that were ameliorated by the Ferroptosis inhibitor Ferrostatin-1. Furthermore, the depletion of Serpina3k exacerbated senescence and Collagen deposition through the activation of the cGAS-STING-PERK axis, effects that can be reversed via the overexpression of Serpina3k or the knockdown of STING. The protective effect of SERPINA3K was also demonstrated in vivo through AAV9-mediated cardiomyocyte-specific overexpression in middle-aged mice, which attenuated the cGAS-STING-PERK axis and mitigated age-related fibrosis. These results strongly demonstrated that FTL1 and SERPINA3K function as key regulators of cardiac aging. Collectively, this study provides a valuable region-resolved proteomic atlas of cardiac aging and identifies key protein regulators, thereby uncovering potential targets for cardio-protective interventions against age-related cardiovascular disorders.

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