{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T16:02:27Z","timestamp":1792252947953,"version":"4.4.0"},"reference-count":29,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T00:00:00Z","timestamp":1664150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Disciplinary Fund of Wuhan Central Hospital","award":["2021XK060"],"award-info":[{"award-number":["2021XK060"]}]},{"name":"Disciplinary Fund of Wuhan Central Hospital","award":["2021XK062"],"award-info":[{"award-number":["2021XK062"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>A previous study found that transmembrane protein 43 (TMEM43) was highly associated with arrhythmogenic right ventricular dysplasia\/cardiomyopathy. However, as a transmembrane protein, TMEM43 may be involved in ferroptosis in cardiovascular disease. In this study, we aimed to explore the role of TMEM43 in lipopolysaccharide (LPS)-induced cardiac injury and the underlying mechanism. Mice were injected with LPS (10 mg\/kg) for 12 h to generate experimental sepsis. Mice were also subjected to AAV9-shTMEM43 to knock down TMEM43 or AAV9-TMEM43 to overexpress TMEM43 in hearts. H9c2 rat cardiomyocytes were also transfected with Ad-TMEM43 or TMEM43 siRNA to overexpress\/knock down TMEM43. As a result, TMEM43 knockdown in hearts deteriorated LPS-induced mouse cardiac injury and dysfunction. LPS increased cardiac ferroptosis as assessed by malonaldehyde (MDA) and cardiac iron density, which were aggravated by TMEM43 knockdown. Moreover, TMEM43 overexpression alleviated LPS-induced cardiac injury, dysfunction, and ferroptosis. In vitro experiments showed that TMEM43 overexpression inhibited LPS-induced lipid peroxidation and cardiomyocyte injury while TMEM43 knockdown aggravated LPS-induced ferroptosis and injury in cardiomyocytes. Mechanistically, LPS increased the expression of P53 and ferritin but decreased the level of Gpx4 and SLC7A11. TMEM43 could inhibit the level of P53 and ferritin enhanced the level of Gpx4 and SLC7A11. Furthermore, ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, could protect against LPS-induced cardiac injury and also counteracted the deteriorating effects of TMEM43 silencing in the heart. Based on these findings, we concluded that TMEM43 protects against sepsis-induced cardiac injury via inhibiting ferroptosis in mice. By targeting ferroptosis in cardiomyocytes, TMEM43 may be a therapeutic strategy for preventing sepsis in the future.<\/jats:p>","DOI":"10.3390\/cells11192992","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T21:23:27Z","timestamp":1664313807000},"page":"2992","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["TMEM43 Protects against Sepsis-Induced Cardiac Injury via Inhibiting Ferroptosis in Mice"],"prefix":"10.3390","volume":"11","author":[{"given":"Zhen","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Emergency, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Gui","sequence":"additional","affiliation":[{"name":"Department of Emergency, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Emergency, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Emergency, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Emergency, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Emergency, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Emergency, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fen","family":"Ai","sequence":"additional","affiliation":[{"name":"Department of Emergency, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Emergency, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/s41569-020-00492-2","article-title":"Pathophysiology of sepsis-induced cardiomyopathy","volume":"18","author":"Hollenberg","year":"2021","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s11886-020-01277-2","article-title":"Sepsis-Induced Cardiomyopathy: A Comprehensive Review","volume":"22","author":"Sternberg","year":"2020","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.bbadis.2018.10.011","article-title":"The role of mitochondria in sepsis-induced cardiomyopathy","volume":"1865","author":"Stanzani","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.3389\/fimmu.2017.01021","article-title":"Sepsis-Induced Cardiomyopathy: Mechanisms and Treatments","volume":"8","author":"Liu","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1097\/CM9.0000000000000929","article-title":"Induction and deduction in sepsis-induced cardiomyopathy: Five typical categories","volume":"133","author":"Wang","year":"2020","journal-title":"Chin. Med. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8832043","DOI":"10.1155\/2020\/8832043","article-title":"Posttranslational Modifications in Ferroptosis","volume":"2020","author":"Wei","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.7150\/thno.54113","article-title":"Ferroptosis as a novel therapeutic target for cardiovascular disease","volume":"11","author":"Wu","year":"2021","journal-title":"Theranostics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"104919","DOI":"10.1016\/j.phrs.2020.104919","article-title":"The Application of Ferroptosis in Diseases","volume":"159","author":"Qiu","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/cdd.2015.158","article-title":"Ferroptosis: Process and function","volume":"23","author":"Xie","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"105466","DOI":"10.1016\/j.phrs.2021.105466","article-title":"Ferroptosis and its emerging roles in cardiovascular diseases","volume":"166","author":"Li","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.1038\/s41418-020-0528-x","article-title":"Inhibitor of apoptosis-stimulating protein of p53 inhibits ferroptosis and alleviates intestinal ischemia\/reperfusion-induced acute lung injury","volume":"27","author":"Li","year":"2020","journal-title":"Cell Death Differ."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.yjmcc.2020.10.010","article-title":"HSF1 functions as a key defender against palmitic acid-induced ferroptosis in cardiomyocytes","volume":"150","author":"Wang","year":"2021","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.freeradbiomed.2020.08.009","article-title":"Ferritinophagy-mediated ferroptosis is involved in sepsis-induced cardiac injury","volume":"160","author":"Li","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e21994","DOI":"10.1096\/fj.202100800R","article-title":"Aberrant accumulation of TMEM43 accompanied by perturbed transmural gene expression in arrhythmogenic cardiomyopathy","volume":"35","author":"Shinomiya","year":"2021","journal-title":"FASEB J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1007\/s13238-018-0563-2","article-title":"TMEM43-S358L mutation enhances NF-kappaB-TGFbeta signal cascade in arrhythmogenic right ventricular dysplasia\/cardiomyopathy","volume":"10","author":"Zheng","year":"2019","journal-title":"Protein Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1093\/cvr\/cvaa300","article-title":"Haploinsufficiency of Tmem43 in cardiac myocytes activates the DNA damage response pathway leading to a late-onset senescence-associated pro-fibrotic cardiomyopathy","volume":"117","author":"Rouhi","year":"2021","journal-title":"Cardiovasc. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1152\/physiolgenomics.00066.2021","article-title":"Systems genetics analysis defines importance of TMEM43\/LUMA for cardiac- and metabolic-related pathways","volume":"54","author":"Gu","year":"2022","journal-title":"Physiol. Genom."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3322","DOI":"10.1016\/j.bbadis.2018.07.019","article-title":"LAZ3 protects cardiac remodeling in diabetic cardiomyopathy via regulating miR-21\/PPARa signaling","volume":"1864","author":"Gao","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"110108","DOI":"10.1016\/j.biopha.2020.110108","article-title":"The emerging role of ferroptosis in inflammation","volume":"127","author":"Sun","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"154840","DOI":"10.1016\/j.metabol.2021.154840","article-title":"FUNDC1 insufficiency sensitizes high fat diet intake-induced cardiac remodeling and contractile anomaly through ACSL4-mediated ferroptosis","volume":"122","author":"Pei","year":"2021","journal-title":"Metabolism"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9929687","DOI":"10.1155\/2021\/9929687","article-title":"Ferroptosis: Opportunities and Challenges in Myocardial Ischemia-Reperfusion Injury","volume":"2021","author":"Zhao","year":"2021","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/iub.1895","article-title":"P53-dependent induction of ferroptosis is required for artemether to alleviate carbon tetrachloride-induced liver fibrosis and hepatic stellate cell activation","volume":"71","author":"Wang","year":"2019","journal-title":"IUBMB Life"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.2147\/JIR.S307081","article-title":"Role of Ferroptosis in Lung Diseases","volume":"14","author":"Xu","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/s41419-020-2298-2","article-title":"Ferroptosis: Past, present and future","volume":"11","author":"Li","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"789517","DOI":"10.3389\/fcell.2021.789517","article-title":"Recent Progress of Ferroptosis in Lung Diseases","volume":"9","author":"Yu","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature14344","article-title":"Ferroptosis as a p53-mediated activity during tumour suppression","volume":"520","author":"Jiang","year":"2015","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/s41556-019-0305-6","article-title":"ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway","volume":"21","author":"Chu","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/s41419-019-2064-5","article-title":"ROS-mediated autophagy increases intracellular iron levels and ferroptosis by ferritin and transferrin receptor regulation","volume":"10","author":"Park","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1038\/cr.2016.95","article-title":"Ferroptosis is an autophagic cell death process","volume":"26","author":"Gao","year":"2016","journal-title":"Cell Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/19\/2992\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:39:43Z","timestamp":1760143183000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/19\/2992"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,26]]},"references-count":29,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["cells11192992"],"URL":"https:\/\/doi.org\/10.3390\/cells11192992","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,26]]}}}