{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:10:32Z","timestamp":1785409832968,"version":"3.56.0"},"reference-count":47,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82570408"],"award-info":[{"award-number":["82570408"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170354"],"award-info":[{"award-number":["82170354"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82570408"],"award-info":[{"award-number":["82570408"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82170354"],"award-info":[{"award-number":["82170354"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Fund Project of Changning Health Commission","award":["2024QN01"],"award-info":[{"award-number":["2024QN01"]}]},{"name":"Shanghai Science and Technology Innovation Action Plan star project-Sail special project","award":["24YF2740000"],"award-info":[{"award-number":["24YF2740000"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCDD"],"abstract":"<jats:p>Myocardial ischemia\u2013reperfusion (I\/R) injury is a frequent complication of acute myocardial infarction (AMI), yet clinical biomarkers and targets remain limited. Although tRNA-derived small RNAs (tsRNAs) are emerging cardiovascular regulators, their roles in I\/R injury are not fully elucidated. We identified tsRNA-3025a via sequencing in mouse I\/R models and validated its clinical significance. Circulating tsRNA-3025a was significantly upregulated in AMI and unstable angina patients, independently predicting adverse events within 30 days. Functionally, tsRNA-3025a exacerbated apoptosis and mitochondrial dysfunction in vitro, while its in vivo silencing reduced infarct size, improved cardiac function and increased the proportion of Ki67- and pH3-positive cardiomyocytes. Mechanistically, tsRNA-3025a aggravated injury by targeting PIK3C2A, thereby suppressing autophagosome formation and impairing protective autophagic flux during reperfusion. In conclusion, circulating tsRNA-3025a serves as a prognostic biomarker for post-PCI patients. Targeting tsRNA-3025a attenuates myocardial I\/R injury and restores myocardial regeneration and repair by regulating PIK3C2A-mediated protective autophagy flux.<\/jats:p>","DOI":"10.3390\/jcdd13060266","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T05:59:47Z","timestamp":1781503187000},"page":"266","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["tsRNA-3025a Impairs Mitochondrial Function and Autophagy to Inhibit Myocardial Regeneration and Repair Following Ischemia\u2013Reperfusion Injury"],"prefix":"10.3390","volume":"13","author":[{"given":"Zehao","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Cardiology & Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200051, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Jiangnan University Medical Center (Wuxi No. 2 People\u2019s Hospital), Wuxi School of Medicine, Jiangnan University, Wuxi 214043, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Jiangnan University Medical Center (Wuxi No. 2 People\u2019s Hospital), Wuxi School of Medicine, Jiangnan University, Wuxi 214043, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology & Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200051, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaixuan","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Cardiology & Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200051, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumo","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology & Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200051, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7754-2367","authenticated-orcid":false,"given":"Ying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200051, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology & Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200051, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingmei","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Cardiology & Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200051, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.1016\/S0735-1097(24)04310-9","article-title":"Global prevalence of coronary artery disease: An update from the global burden of disease study","volume":"83","author":"Stark","year":"2024","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.amjmed.2014.04.015","article-title":"The Epidemic of the 20th Century: Coronary Heart Disease","volume":"127","author":"Dalen","year":"2014","journal-title":"Am. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0140-6736(15)00551-6","article-title":"Cause-Specific Mortality for 240 Causes in China during 1990\u20132013: A Systematic Subnational Analysis for the Global Burden of Disease Study 2013","volume":"387","author":"Zhou","year":"2016","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/S0140-6736(21)02391-6","article-title":"Acute Coronary Syndromes","volume":"399","author":"Bergmark","year":"2022","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1016\/j.cell.2022.04.004","article-title":"Atherosclerosis: Recent Developments","volume":"185","author":"Lusis","year":"2022","journal-title":"Cell"},{"key":"ref_6","first-page":"62","article-title":"B-Type Natriuretic Peptide as a Predictor of Ischemia\/Reperfusion Injury Immediately after Myocardial Reperfusion in Patients with ST-Segment Elevation Acute Myocardial Infarction","volume":"5","author":"Arakawa","year":"2016","journal-title":"Eur. Heart J. Acute Cardiovasc. Care"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2704","DOI":"10.1093\/eurheartj\/ehx165","article-title":"Non-Coding RNAs in Cardiovascular Diseases: Diagnostic and Therapeutic Perspectives","volume":"39","author":"Poller","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.yjmcc.2016.03.015","article-title":"Cardiac-Specific miRNA in Cardiogenesis, Heart Function, and Cardiac Pathology (with Focus on Myocardial Infarction)","volume":"94","author":"Chistiakov","year":"2016","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"118788","DOI":"10.1016\/j.lfs.2020.118788","article-title":"Circular RNA Arhgap12 Modulates Doxorubicin-Induced Cardiotoxicity by Sponging miR-135a-5p","volume":"265","author":"Wang","year":"2021","journal-title":"Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/j.jacbts.2022.06.004","article-title":"LncRNA-ZFAS1 Promotes Myocardial Ischemia-Reperfusion Injury Through DNA Methylation-Mediated Notch1 Down-Regulation in Mice","volume":"7","author":"Li","year":"2022","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1007\/s00109-021-02132-9","article-title":"PiRNA Pathway in the Cardiovascular System: A Novel Regulator of Cardiac Differentiation, Repair and Regeneration","volume":"99","author":"Zhou","year":"2021","journal-title":"J. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1007\/s00109-018-1693-y","article-title":"Transfer RNA-Derived Fragments and tRNA Halves: Biogenesis, Biological Functions and Their Roles in Diseases","volume":"96","author":"Shen","year":"2018","journal-title":"J. Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1002\/jcp.29057","article-title":"tiRNAs: A Novel Class of Small Noncoding RNAs That Helps Cells Respond to Stressors and Plays Roles in Cancer Progression","volume":"235","author":"Tao","year":"2020","journal-title":"J. Cell. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/s41392-020-00217-4","article-title":"Action Mechanisms and Research Methods of tRNA-Derived Small RNAs","volume":"5","author":"Xie","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"461","DOI":"10.7150\/thno.51963","article-title":"tRNA-Derived Fragments: Mechanisms Underlying Their Regulation of Gene Expression and Potential Applications as Therapeutic Targets in Cancers and Virus Infections","volume":"11","author":"Yu","year":"2021","journal-title":"Theranostics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5250","DOI":"10.1093\/nar\/gky189","article-title":"Drosophila tsRNAs Preferentially Suppress General Translation Machinery via Antisense Pairing and Participate in Cellular Starvation Response","volume":"46","author":"Luo","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"16930","DOI":"10.1074\/jbc.RA119.009272","article-title":"Angiogenin Generates Specific Stress-Induced tRNA Halves and Is Not Involved in tRF-3\u2013Mediated Gene Silencing","volume":"294","author":"Su","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1007\/s12265-022-10322-0","article-title":"tRNA-Derived Small RNAs: Novel Insights into the Pathogenesis and Treatment of Cardiovascular Diseases","volume":"16","author":"Wang","year":"2023","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.trsl.2025.04.002","article-title":"tiRNA-HAR Contributes to Ischemic Myocardial Injury via Facilitating HuR-Mediated Stability of P53","volume":"280","author":"Wang","year":"2025","journal-title":"Transl. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1002\/jcsm.13187","article-title":"tRNA-derived Small RNA, 5\u2019tiRNA-Gly-CCC, Promotes Skeletal Muscle Regeneration through the Inflammatory Response","volume":"14","author":"Shen","year":"2023","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"114809","DOI":"10.1016\/j.yexcr.2025.114809","article-title":"A tRNA-Derived Fragment tiRNA-Met-CAT-002 Induced by Myocardial Ischemia\/Reperfusion Injury Inhibits Cardiomyocyte Autophagy by Regulating Bnip3","volume":"453","author":"Deng","year":"2025","journal-title":"Exp. Cell Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1007\/s00418-010-0748-0","article-title":"Autophagy in Myocardium of Murine Hearts Subjected to Ischemia Followed by Reperfusion","volume":"134","author":"French","year":"2010","journal-title":"Histochem. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1093\/cvr\/cvp384","article-title":"Cardioprotection by Resveratrol: A Novel Mechanism via Autophagy Involving the mTORC2 Pathway","volume":"86","author":"Gurusamy","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.molcel.2018.06.042","article-title":"Autoregulation of Class II Alpha PI3K Activity by Its Lipid-Binding PX-C2 Domain Module","volume":"71","author":"Wang","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"113408","DOI":"10.1016\/j.celrep.2023.113408","article-title":"Pan-Cancer tRNA-Derived Fragment CAT1 Coordinates RBPMS to Stabilize NOTCH2 mRNA to Promote Tumorigenesis","volume":"42","author":"Yu","year":"2023","journal-title":"Cell Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s13046-021-01836-7","article-title":"A Specific tRNA Half, 5\u2019tiRNA-His-GTG, Responds to Hypoxia via the HIF1\u03b1\/ANG Axis and Promotes Colorectal Cancer Progression by Regulating LATS2","volume":"40","author":"Tao","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1261\/rna.066126.118","article-title":"tRNA Fragments (tRFs) Guide Ago to Regulate Gene Expression Post-Transcriptionally in a Dicer-Independent Manner","volume":"24","author":"Kuscu","year":"2018","journal-title":"RNA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.tcb.2019.01.001","article-title":"Class II PI3K Functions in Cell Biology and Disease","volume":"29","author":"Gulluni","year":"2019","journal-title":"Trends Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1056\/NEJMra071667","article-title":"Myocardial Reperfusion Injury","volume":"357","author":"Yellon","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nrg.2016.160","article-title":"Genetics of Coronary Artery Disease: Discovery, Biology and Clinical Translation","volume":"18","author":"Khera","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Marinescu, M.-C., Lazar, A.-L., Marta, M.M., Cozma, A., and Catana, C.-S. (2022). Non-Coding RNAs: Prevention, Diagnosis, and Treatment in Myocardial Ischemia\u2013Reperfusion Injury. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052728"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s00439-025-02742-0","article-title":"Comprehensive Profiling of tsRNAs in Acute Coronary Syndrome: Expression Patterns, Clinical Correlations, and Functional Insights","volume":"144","author":"He","year":"2025","journal-title":"Hum. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.7150\/ijms.106114","article-title":"Screening and Evaluation of tRF-Glu-CTC-013 as a Biomarker and Key Regulator in the Development of Cardiac Hypertrophy","volume":"22","author":"Li","year":"2025","journal-title":"Int. J. Med. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/ehf2.13144","article-title":"Heart Failure after Myocardial Infarction: Incidence and Predictors","volume":"8","author":"Stehlik","year":"2021","journal-title":"ESC Heart Fail."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1186\/s13045-022-01388-z","article-title":"A Novel tRNA-Derived Fragment tRF-3022b Modulates Cell Apoptosis and M2 Macrophage Polarization via Binding to Cytokines in Colorectal Cancer","volume":"15","author":"Lu","year":"2022","journal-title":"J. Hematol. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s11658-022-00398-6","article-title":"tRF-3013b Inhibits Gallbladder Cancer Proliferation by Targeting TPRG1L","volume":"27","author":"Zou","year":"2022","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1038\/s41388-024-02991-9","article-title":"tiRNA-Val-CAC-2 Interacts with FUBP1 to Promote Pancreatic Cancer Metastasis by Activating c MYC Transcription","volume":"43","author":"Xiong","year":"2024","journal-title":"Oncogene"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Merrill, N.M., Schipper, J.L., Karnes, J.B., Kauffman, A.L., Martin, K.R., and MacKeigan, J.P. (2017). PI3K-C2\u03b1 Knockdown Decreases Autophagy and Maturation of Endocytic Vesicles. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0184909"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Soliman, S.E., Abouelenin, M.A.H., Samy, N.I., Omar, M.M., and Alrefai, A.A. (2023). Various Expressions of PIK3C2A and TXNIP Genes and Their Potential Role as Independent Risk Factors for Chronic Stable Angina and Acute Coronary Syndrome. Biomolecules, 13.","DOI":"10.3390\/biom13020302"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e15061","DOI":"10.1097\/MD.0000000000015061","article-title":"Low Expression of PIK3C2A Gene","volume":"98","author":"Tan","year":"2019","journal-title":"Medicine"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s10495-022-01786-1","article-title":"Regulation of Autophagy of the Heart in Ischemia and Reperfusion","volume":"28","author":"Popov","year":"2023","journal-title":"Apoptosis"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1159\/000354464","article-title":"Acetylcholine Mediates AMPK-Dependent Autophagic Cytoprotection in H9c2 Cells During Hypoxia\/Reoxygenation Injury","volume":"32","author":"Zhao","year":"2013","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.1161\/CIRCULATIONAHA.111.041814","article-title":"Impaired Autophagosome Clearance Contributes to Cardiomyocyte Death in Ischemia\/Reperfusion Injury","volume":"125","author":"Ma","year":"2012","journal-title":"Circulation"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejphar.2015.05.028","article-title":"Berberine Alleviates Cardiac Ischemia\/Reperfusion Injury by Inhibiting Excessive Autophagy in Cardiomyocytes","volume":"762","author":"Huang","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"345","DOI":"10.33549\/physiolres.933996","article-title":"Hydrogen Sulfide Plays an Important Protective Role by Influencing Autophagy in Diseases","volume":"68","author":"Wang","year":"2019","journal-title":"Physiol. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1007\/s00395-021-00894-4","article-title":"The Zinc Transporter ZIP7 (Slc39a7) Controls Myocardial Reperfusion Injury by Regulating Mitophagy","volume":"116","author":"Zhang","year":"2021","journal-title":"Basic Res. Cardiol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Ji, W., Wei, S., Hao, P., Xing, J., Yuan, Q., Wang, J., Xu, F., and Chen, Y. (2016). Aldehyde Dehydrogenase 2 Has Cardioprotective Effects on Myocardial Ischaemia\/Reperfusion Injury via Suppressing Mitophagy. Front. Pharmacol., 7.","DOI":"10.3389\/fphar.2016.00101"}],"container-title":["Journal of Cardiovascular Development and Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2308-3425\/13\/6\/266\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T06:34:27Z","timestamp":1781505267000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2308-3425\/13\/6\/266"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,12]]},"references-count":47,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["jcdd13060266"],"URL":"https:\/\/doi.org\/10.3390\/jcdd13060266","relation":{},"ISSN":["2308-3425"],"issn-type":[{"value":"2308-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,12]]}}}