{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:09:41Z","timestamp":1791490181231,"version":"4.3.4"},"reference-count":76,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:00:00Z","timestamp":1767916800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:00:00Z","timestamp":1767916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Key scientific and technological innovation projects of Wenzho"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Exp Mol Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Acute limb ischemia\u2013reperfusion injury (ALIRI) prominently involves microvascular dysfunction, with notable contributions from damage to microvascular endothelial cells (MECs). Previous research suggests that the mechanosensitive ion channel Piezo1 becomes active in response to mechanical stress conditions, including ischemia and trauma. However, its precise function within the ALIRI context remains elusive. Notably, the expression of Piezo1 was markedly elevated postreperfusion in mouse hind limb ischemia\/reperfusion (I\/R) models, implicating its crucial involvement in limb survival. Employing specific inhibitors of cell death pathways, the study delineated key molecular drivers of ferroptosis during limb damage. Here evaluations of limb vitality, western blot, quantitative PCR and immunofluorescence implicated that activation of Piezo1 by its agonist exacerbates I\/R-induced microvascular perfusion deficits, tissue swelling, skeletal muscle damage and increased tissue infarction and MECs damage. Conversely, these detrimental impacts were mitigated through pharmacological blockade of Piezo1 or specific deletion of\n                    <jats:italic>Piezo1<\/jats:italic>\n                    in MECs. Comprehensive untargeted metabolomic analysis revealed significant changes primarily in glycerophospholipid and arachidonic acid metabolism pathways. Further experiments demonstrated that RNA interference-mediated inhibition of cytosolic phospholipase A2 (cPLA2) and acyl-CoA synthetase long-chain family member 4 (ACSL4) negated the protective effects against ferroptosis and limb damage that were observed with Piezo1 deletion. Moreover, this study confirmed that protein kinase C phosphorylates ACSL4, which mediates Piezo1-induced ferroptosis and exacerbates limb damage, as shown through immunoprecipitation studies. In summary, Piezo1 contributes to the exacerbation of microvascular and skeletal muscle damage in ALIRI by facilitating the cPLA2-dependent release of arachidonic acid and promoting ACSL4-driven lipid peroxidation, thereby intensifying ferroptosis in MECs.\n                  <\/jats:p>","DOI":"10.1038\/s12276-025-01616-9","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T02:39:09Z","timestamp":1767926349000},"page":"143-160","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Piezo1 activation in endothelial cells aggravates microvascular ischemia\u2013reperfusion injury in limbs by enhancing ferroptosis"],"prefix":"10.1038","volume":"58","author":[{"given":"Fan-feng","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin-he","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-chang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyi","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anyu","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenghu","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keqing","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zimiao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zili","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kailiang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7374-6506","authenticated-orcid":false,"given":"Jian","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"1616_CR1","doi-asserted-by":"publisher","first-page":"6829","DOI":"10.2147\/IJN.S174030","volume":"13","author":"J Xu","year":"2018","unstructured":"Xu, J. et al. Chitosan-microcapsulated insulin alleviates mesenteric microcirculation dysfunction via modulating COX-2 and VCAM-1 expression in rats with diabetes mellitus. Int. J. Nanomed. 13, 6829\u20136837 (2018).","journal-title":"Int. J. Nanomed."},{"key":"1616_CR2","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1002\/jmri.26308","volume":"49","author":"T Ganesh","year":"2018","unstructured":"Ganesh, T. et al. Assessment of microvascular dysfunction in acute limb ischemia-reperfusion injury. J. Magnet. Reson. Imaging 49, 1174\u20131185 (2018).","journal-title":"J. Magnet. Reson. Imaging"},{"key":"1616_CR3","first-page":"19","volume":"5","author":"LF Rodella","year":"2013","unstructured":"Rodella, L. F. et al. Vascular endothelial cells and dysfunctions: role of melatonin. Front. Biosci. 5, 19\u201329 (2013).","journal-title":"Front. Biosci."},{"key":"1616_CR4","doi-asserted-by":"publisher","DOI":"10.1186\/s13017-015-0025-6","volume":"10","author":"K Stanger","year":"2015","unstructured":"Stanger, K., Horch, R. E. & Dragu, A. Severe mutilating injuries with complex macroamputations of the upper extremity\u2014is it worth the effort? World J. Emerg. Surg. 10, 30 (2015).","journal-title":"World J. Emerg. Surg."},{"key":"1616_CR5","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1001\/jamasurg.2019.1050","volume":"154","author":"SJ Mortensen","year":"2019","unstructured":"Mortensen, S. J. et al. Diagnostic modalities for acute compartment syndrome of the extremities. JAMA Surg 154, 655\u2013665 (2019).","journal-title":"JAMA Surg"},{"key":"1616_CR6","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1038\/s41392-022-01172-y","volume":"7","author":"F Chen","year":"2022","unstructured":"Chen, F. et al. FGF21 alleviates microvascular damage following limb ischemia\/reperfusion injury by TFEB-mediated autophagy enhancement and anti-oxidative response. Signal Transduct. Target. Ther. 7, 349 (2022).","journal-title":"Signal Transduct. Target. Ther."},{"key":"1616_CR7","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/0735-1097(89)90526-3","volume":"13","author":"MB Forman","year":"1989","unstructured":"Forman, M. B., Puett, D. W. & Virmani, R. Endothelial and myocardial injury during ischemia and reperfusion: pathogenesis and therapeutic implications. J. Am. Coll. Cardiol. 13, 450\u2013459 (1989).","journal-title":"J. Am. Coll. Cardiol."},{"key":"1616_CR8","doi-asserted-by":"publisher","first-page":"eaba8968","DOI":"10.1126\/sciadv.aba8968","volume":"6","author":"N Verma","year":"2020","unstructured":"Verma, N. et al. Synthetic lethal combination targeting BET uncovered intrinsic susceptibility of TNBC to ferroptosis. Sci. Adv. 6, eaba8968 (2020).","journal-title":"Sci. Adv."},{"key":"1616_CR9","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1161\/CIRCULATIONAHA.122.060257","volume":"147","author":"W Cai","year":"2023","unstructured":"Cai, W. et al. Alox15\/15-HpETE aggravates myocardial ischemia-reperfusion injury by promoting cardiomyocyte ferroptosis. Circulation 147, 1444\u20131460 (2023).","journal-title":"Circulation"},{"key":"1616_CR10","doi-asserted-by":"publisher","first-page":"6437","DOI":"10.3390\/ijms23126437","volume":"23","author":"Z Yang","year":"2022","unstructured":"Yang, Z. et al. Molecular characterization, tissue distribution profile, and nutritional regulation of ACSL gene family in golden pompano (Trachinotus ovatus). Int. J. Mol. Sci. 23, 6437 (2022).","journal-title":"Int. J. Mol. Sci."},{"key":"1616_CR11","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/nchembio.2239","volume":"13","author":"S Doll","year":"2016","unstructured":"Doll, S. et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 13, 91\u201398 (2016).","journal-title":"Nat. Chem. Biol."},{"key":"1616_CR12","doi-asserted-by":"publisher","first-page":"112539","DOI":"10.1016\/j.intimp.2024.112539","volume":"138","author":"Y Tang","year":"2024","unstructured":"Tang, Y. et al. TRPV1\/cPLA2\/AA pathway contributes to ferroptosis-mediated acute liver injury in heatstroke. Int. Immunopharmacol. 138, 112539 (2024).","journal-title":"Int. Immunopharmacol."},{"key":"1616_CR13","doi-asserted-by":"publisher","first-page":"730","DOI":"10.3390\/biom14060730","volume":"14","author":"KG Lyamzaev","year":"2024","unstructured":"Lyamzaev, K. G. et al. Exogenous iron induces mitochondrial lipid peroxidation, lipofuscin accumulation, and ferroptosis in H9c2 cardiomyocytes. Biomolecules 14, 730 (2024).","journal-title":"Biomolecules"},{"key":"1616_CR14","doi-asserted-by":"publisher","first-page":"122438","DOI":"10.1016\/j.envpol.2023.122438","volume":"336","author":"W Shi","year":"2023","unstructured":"Shi, W. et al. Co-exposure to Fe, Zn, and Cu induced neuronal ferroptosis with associated lipid metabolism disorder via the ERK\/cPLA2\/AA pathway. Environm. Pollut. 336, 122438 (2023).","journal-title":"Environm. Pollut."},{"key":"1616_CR15","doi-asserted-by":"publisher","first-page":"155288","DOI":"10.1016\/j.phymed.2023.155288","volume":"124","author":"Z Chen","year":"2024","unstructured":"Chen, Z. et al. Dual role of Nrf2\/HO-1 pathway in Z-ligustilide-induced ferroptosis against AML cells. Phytomedicine 124, 155288 (2024).","journal-title":"Phytomedicine"},{"key":"1616_CR16","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/s41556-021-00818-3","volume":"24","author":"H-L Zhang","year":"2022","unstructured":"Zhang, H.-L. et al. PKC\u03b2 II phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat. Cell Biol. 24, 88\u201398 (2022).","journal-title":"Nat. Cell Biol."},{"key":"1616_CR17","doi-asserted-by":"publisher","first-page":"2284","DOI":"10.1038\/s41418-019-0299-4","volume":"26","author":"Y Li","year":"2019","unstructured":"Li, Y. et al. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia\/reperfusion. Cell Death Differ 26, 2284\u20132299 (2019).","journal-title":"Cell Death Differ"},{"key":"1616_CR18","doi-asserted-by":"publisher","first-page":"733.e731","DOI":"10.1016\/j.ajog.2020.05.012","volume":"223","author":"S Afrin","year":"2020","unstructured":"Afrin, S. et al. Simvastatin ameliorates altered mechanotransduction in uterine leiomyoma cells. Am. J. Obstet. Gynecol. 223, 733.e731\u2013733.e714 (2020).","journal-title":"Am. J. Obstet. Gynecol."},{"key":"1616_CR19","doi-asserted-by":"publisher","first-page":"C1","DOI":"10.1152\/ajpcell.00559.2003","volume":"287","author":"H Huang","year":"2004","unstructured":"Huang, H., Kamm, R. D. & Lee, R. T. Cell mechanics and mechanotransduction: pathways, probes, and physiology. Am. J. Physiol. Cell Physiol. 287, C1\u2013-C11 (2004).","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"1616_CR20","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1126\/science.1193270","volume":"330","author":"B Coste","year":"2010","unstructured":"Coste, B. et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330, 55\u201360 (2010).","journal-title":"Science"},{"key":"1616_CR21","doi-asserted-by":"publisher","first-page":"588259","DOI":"10.3389\/fphar.2020.588259","volume":"11","author":"L Zhang","year":"2021","unstructured":"Zhang, L. et al. Ginsenoside Rg1-notoginsenoside R1-protocatechuic aldehyde reduces atherosclerosis and attenuates low-shear stress-induced vascular endothelial cell dysfunction. Front. Pharmacol. 11, 588259 (2021).","journal-title":"Front. Pharmacol."},{"key":"1616_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04194-9","volume":"9","author":"JM Romac","year":"2018","unstructured":"Romac, J. M. et al. Piezo1 is a mechanically activated ion channel and mediates pressure induced pancreatitis. Nat. Commun. 9, 1715 (2018).","journal-title":"Nat. Commun."},{"key":"1616_CR23","doi-asserted-by":"publisher","first-page":"102309","DOI":"10.1016\/j.redox.2022.102309","volume":"52","author":"Y Peng","year":"2022","unstructured":"Peng, Y. et al. Mechano-signaling via Piezo1 prevents activation and p53-mediated senescence of muscle stem cells. Redox Biol. 52, 102309 (2022).","journal-title":"Redox Biol."},{"key":"1616_CR24","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.jare.2022.01.004","volume":"41","author":"S Wang","year":"2022","unstructured":"Wang, S. et al. Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx. J. Adv. Res. 41, 63\u201375 (2022).","journal-title":"J. Adv. Res."},{"key":"1616_CR25","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.tibs.2016.09.004","volume":"42","author":"J Wu","year":"2017","unstructured":"Wu, J., Lewis, A. H. & Grandl, J. Touch, tension, and transduction\u2014the function and regulation of Piezo ion channels. Trends Biochem. Sci. 42, 57\u201371 (2017).","journal-title":"Trends Biochem. Sci."},{"key":"1616_CR26","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1016\/j.gendis.2022.08.015","volume":"10","author":"J Huang","year":"2023","unstructured":"Huang, J. et al. The Janus-faced role of Piezo1 in cardiovascular health under mechanical stimulation. Genes Dis 10, 1956\u20131968 (2023).","journal-title":"Genes Dis"},{"key":"1616_CR27","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1002\/cem.2736","volume":"29","author":"M Farr\u00e9s","year":"2015","unstructured":"Farr\u00e9s, M. et al. Comparison of the variable importance in projection (VIP) and of the selectivity ratio (SR) methods for variable selection and interpretation. J. Chemometrics 29, 528\u2013536 (2015).","journal-title":"J. Chemometrics"},{"key":"1616_CR28","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1093\/bioinformatics\/btp053","volume":"25","author":"DJ McCarthy","year":"2009","unstructured":"McCarthy, D. J. & Smyth, G. K. Testing significance relative to a fold-change threshold is a TREAT[J]. Bioinformatics 25, 765\u2013771 (2009).","journal-title":"Bioinformatics"},{"key":"1616_CR29","doi-asserted-by":"publisher","first-page":"82","DOI":"10.3892\/ijo.2021.5262","volume":"59","author":"P King","year":"2021","unstructured":"King, P. et al. Regulation of gliomagenesis and stemness through acid sensor ASIC1a. Int. J. Oncol 59, 82 (2021).","journal-title":"Int. J. Oncol"},{"key":"1616_CR30","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1161\/CIRCRESAHA.115.306642","volume":"117","author":"V Ohanyan","year":"2015","unstructured":"Ohanyan, V. et al. Requisite role of Kv1.5 channels in coronary metabolic dilation. Circ. Res. 117, 612\u2013621 (2015).","journal-title":"Circ. Res."},{"key":"1616_CR31","doi-asserted-by":"publisher","first-page":"9911167","DOI":"10.1155\/2022\/9911167","volume":"2022","author":"Y Wang","year":"2022","unstructured":"Wang, Y. et al. Postconditioning with irisin attenuates lung ischemia\/reperfusion injury by suppressing ferroptosis via induction of the Nrf2\/HO-1 signal axis. Oxid. Med. Cell. Longev. 2022, 9911167 (2022).","journal-title":"Oxid. Med. Cell. Longev."},{"key":"1616_CR32","doi-asserted-by":"publisher","first-page":"4340","DOI":"10.7150\/ijbs.85692","volume":"19","author":"F Chen","year":"2023","unstructured":"Chen, F. et al. FGF2 alleviates microvascular ischemia-reperfusion injury by KLF2-mediated ferroptosis inhibition and antioxidant responses. Int. J. Biol. Sci. 19, 4340\u20134359 (2023).","journal-title":"Int. J. Biol. Sci."},{"key":"1616_CR33","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/nchembio.2238","volume":"13","author":"VE Kagan","year":"2016","unstructured":"Kagan, V. E. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 13, 81\u201390 (2016).","journal-title":"Nat. Chem. Biol."},{"key":"1616_CR34","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/s41392-022-00917-z","volume":"7","author":"Q-Z Tuo","year":"2022","unstructured":"Tuo, Q.-Z. et al. Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia\/reperfusion. Signal Transduct. Target. Ther. 7, 59 (2022).","journal-title":"Signal Transduct. Target. Ther."},{"key":"1616_CR35","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.freeradbiomed.2024.02.016","volume":"214","author":"Y Ye","year":"2024","unstructured":"Ye, Y. et al. The ERK-cPLA2-ACSL4 axis mediating M2 macrophages ferroptosis impedes mucosal healing in ulcerative colitis. Free Radic. Biol. Med. 214, 219\u2013235 (2024).","journal-title":"Free Radic. Biol. Med."},{"key":"1616_CR36","doi-asserted-by":"publisher","first-page":"3763","DOI":"10.3390\/ijms23073763","volume":"23","author":"V Chubinskiy-Nadezhdin","year":"2022","unstructured":"Chubinskiy-Nadezhdin, V. et al. Store-operated Ca\u00b2\u207a entry contributes to Piezo1-induced Ca\u00b2\u207a increase in human endometrial stem cells. Int. J. Mol. Sci. 23, 3763 (2022).","journal-title":"Int. J. Mol. Sci."},{"key":"1616_CR37","doi-asserted-by":"publisher","first-page":"2290","DOI":"10.1038\/emboj.2010.126","volume":"29","author":"L Ulmann","year":"2010","unstructured":"Ulmann, L., Hirbec, H. & Rassendren, F. P2X4 receptors mediate PGE2 release by tissue-resident macrophages and initiate inflammatory pain. EMBO J 29, 2290\u20132300 (2010).","journal-title":"EMBO J"},{"key":"1616_CR38","doi-asserted-by":"publisher","first-page":"4146","DOI":"10.3390\/ijms23084146","volume":"23","author":"M Li","year":"2022","unstructured":"Li, M. et al. Activation of TRPV4 induces exocytosis and ferroptosis in human melanoma cells. Int. J. Mol. Sci. 23, 4146 (2022).","journal-title":"Int. J. Mol. Sci."},{"key":"1616_CR39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22336-4","volume":"12","author":"CM Bebber","year":"2021","unstructured":"Bebber, C. M. et al. Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes. Nat. Commun. 12, 2048 (2021).","journal-title":"Nat. Commun."},{"key":"1616_CR40","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1016\/S0969-2126(98)00139-7","volume":"6","author":"RB Sutton","year":"1998","unstructured":"Sutton, R. B. & Sprang, S. R. Structure of the protein kinase C\u03b2 phospholipid-binding C2 domain complexed with Ca2+. Structure 6, 1395\u20131405 (1998).","journal-title":"Structure"},{"key":"1616_CR41","doi-asserted-by":"publisher","first-page":"8246","DOI":"10.1523\/JNEUROSCI.0278-14.2014","volume":"34","author":"L Li","year":"2014","unstructured":"Li, L., Hasan, R. & Zhang, X. The basal thermal sensitivity of the TRPV1 ion channel is determined by PKC II. J. Neurosci. 34, 8246\u20138258 (2014).","journal-title":"J. Neurosci."},{"key":"1616_CR42","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.omtn.2017.03.003","volume":"7","author":"SMJ Welten","year":"2017","unstructured":"Welten, S. M. J. et al. Inhibition of Mef2a enhances neovascularization via post-transcriptional regulation of 14q32 microRNAs miR-329 and miR-494. Mol. Ther. Nucleic Acids 7, 61\u201370 (2017).","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"1616_CR43","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1016\/j.avsg.2022.04.040","volume":"86","author":"P Apichartpiyakul","year":"2022","unstructured":"Apichartpiyakul, P. et al. Mechanisms and interventions on acute lower limb ischemia\/reperfusion injury: a review and insights from cell to clinical investigations. Ann. Vasc. Surg. 86, 452\u2013481 (2022).","journal-title":"Ann. Vasc. Surg."},{"key":"1616_CR44","doi-asserted-by":"publisher","first-page":"3698","DOI":"10.3390\/ijms21103698","volume":"21","author":"T Hara","year":"2020","unstructured":"Hara, T. et al. Cell density-dependent fibroblast growth factor-2 signaling regulates syndecan-4 expression in cultured vascular endothelial cells. Int. J. Mol. Sci. 21, 3698 (2020).","journal-title":"Int. J. Mol. Sci."},{"key":"1616_CR45","doi-asserted-by":"publisher","first-page":"122600","DOI":"10.1016\/j.biomaterials.2024.122600","volume":"309","author":"YT Shih","year":"2024","unstructured":"Shih, Y. T. et al. 3D-printed proangiogenic patches of photo-crosslinked gelatin and polyurethane hydrogels laden with vascular cells for treating vascular ischemic diseases. Biomaterials 309, 122600 (2024).","journal-title":"Biomaterials"},{"key":"1616_CR46","doi-asserted-by":"publisher","first-page":"117081","DOI":"10.1016\/j.biopha.2024.117081","volume":"177","author":"Y Hong","year":"2024","unstructured":"Hong, Y. et al. Berberine as a novel ACSL4 inhibitor to suppress endothelial ferroptosis and atherosclerosis. Biomed. Pharmacother. 177, 117081 (2024).","journal-title":"Biomed. Pharmacother."},{"key":"1616_CR47","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1038\/s41564-023-01523-7","volume":"9","author":"EP Amaral","year":"2023","unstructured":"Amaral, E. P. et al. BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility. Nat. Microbiol. 9, 120\u2013135 (2023).","journal-title":"Nat. Microbiol."},{"key":"1616_CR48","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1038\/s41580-020-00324-8","volume":"22","author":"X Jiang","year":"2021","unstructured":"Jiang, X., Stockwell, B. R. & Conrad, M. Ferroptosis: mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 22, 266\u2013282 (2021).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"1616_CR49","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1021\/acscentsci.7b00589","volume":"4","author":"R Shah","year":"2018","unstructured":"Shah, R., Shchepinov, M. S. & Pratt, D. A. Resolving the role of lipoxygenases in the initiation and execution of ferroptosis. ACS Cent. Sci. 4, 387\u2013396 (2018).","journal-title":"ACS Cent. Sci."},{"key":"1616_CR50","doi-asserted-by":"crossref","unstructured":"Z\u00e1rate, R. et al. Significance of long chain polyunsaturated fatty acids in human health. Clin. Transl. Med. 6 (2017)","DOI":"10.1186\/s40169-017-0153-6"},{"key":"1616_CR51","doi-asserted-by":"publisher","first-page":"799","DOI":"10.3390\/cells8080799","volume":"8","author":"P Lebrero","year":"2019","unstructured":"Lebrero, P. et al. Cellular plasmalogen content does not influence arachidonic acid levels or distribution in macrophages: a role for cytosolic phospholipase A2\u03b3 in phospholipid remodeling. Cells 8, 799 (2019).","journal-title":"Cells"},{"key":"1616_CR52","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1038\/s41392-020-00443-w","volume":"6","author":"B Wang","year":"2021","unstructured":"Wang, B. et al. Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. Signal Trans. Target. Ther. 6, 94 (2021).","journal-title":"Signal Trans. Target. Ther."},{"key":"1616_CR53","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1194\/jlr.M700419-JLR200","volume":"49","author":"Z Pavicevic","year":"2008","unstructured":"Pavicevic, Z., Leslie, C. C. & Malik, K. U. cPLA2 phosphorylation at serine-515 and serine-505 is required for arachidonic acid release in vascular smooth muscle cells. J. Lipid Res. 49, 724\u2013737 (2008).","journal-title":"J. Lipid Res."},{"key":"1616_CR54","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","volume":"171","author":"BR Stockwell","year":"2017","unstructured":"Stockwell, B. R. et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171, 273\u2013285 (2017).","journal-title":"Cell"},{"key":"1616_CR55","doi-asserted-by":"publisher","first-page":"1756","DOI":"10.1089\/ars.2017.7176","volume":"29","author":"MJ Kerins","year":"2018","unstructured":"Kerins, M. J. & Ooi, A. The roles of NRF2 in modulating cellular iron homeostasis. Antiox. Redox Signal. 29, 1756\u20131773 (2018).","journal-title":"Antiox. Redox Signal."},{"key":"1616_CR56","doi-asserted-by":"publisher","first-page":"4542","DOI":"10.1158\/0008-5472.CAN-21-4362","volume":"82","author":"P Pan","year":"2022","unstructured":"Pan, P. et al. HDAC5 loss enhances phospholipid-derived arachidonic acid generation and confers Sensitivity to cPLA2 inhibition in pancreatic cancer. Cancer Res 82, 4542\u20134554 (2022).","journal-title":"Cancer Res"},{"key":"1616_CR57","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1016\/j.cub.2023.02.060","volume":"33","author":"Y Hirata","year":"2023","unstructured":"Hirata, Y. et al. Lipid peroxidation increases membrane tension, Piezo1 gating, and cation permeability to execute ferroptosis. Curr. Biol. 33, 1282\u20131294.e1285 (2023).","journal-title":"Curr. Biol."},{"key":"1616_CR58","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.neuron.2020.07.025","volume":"108","author":"T-T Liu","year":"2020","unstructured":"Liu, T.-T. et al. Piezo1-mediated Ca2+ activities regulate brain vascular pathfinding during development. Neuron 108, 180\u2013192.e185 (2020).","journal-title":"Neuron"},{"key":"1616_CR59","doi-asserted-by":"publisher","first-page":"976482","DOI":"10.3389\/fimmu.2022.976482","volume":"13","author":"S Leng","year":"2022","unstructured":"Leng, S. et al. Ion channel Piezo1 activation promotes aerobic glycolysis in macrophages. Front. Immunol. 13, 976482 (2022).","journal-title":"Front. Immunol."},{"key":"1616_CR60","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.thromres.2022.08.006","volume":"218","author":"J Chen","year":"2022","unstructured":"Chen, J. et al. Upregulation of mechanosensitive channel Piezo1 involved in high shear stress-induced pulmonary hypertension. Thromb. Res. 218, 52\u201363 (2022).","journal-title":"Thromb. Res."},{"key":"1616_CR61","doi-asserted-by":"publisher","first-page":"e184158","DOI":"10.1172\/JCI184158","volume":"135","author":"L Xu","year":"2025","unstructured":"Xu, L. et al. PIEZO1 mediates periostin\u207a myofibroblast activation and pulmonary fibrosis in mice. J. Clin. Invest. 135, e184158 (2025).","journal-title":"J. Clin. Invest."},{"key":"1616_CR62","doi-asserted-by":"publisher","first-page":"e2001611118","DOI":"10.1073\/pnas.2001611118","volume":"118","author":"W Lee","year":"2021","unstructured":"Lee, W. et al. Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis. Proc. Natl Acad. Sci. USA 118, e2001611118 (2021).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1616_CR63","doi-asserted-by":"publisher","first-page":"725275","DOI":"10.3389\/fmolb.2021.725275","volume":"8","author":"JQ Huang","year":"2021","unstructured":"Huang, J. Q. et al. Mechanically activated calcium channel PIEZO1 modulates radiation-induced epithelial-mesenchymal transition by forming a positive feedback with TGF-\u03b21. Front. Mol. Biosci. 8, 725275 (2021).","journal-title":"Front. Mol. Biosci."},{"key":"1616_CR64","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/s41586-019-1485-8","volume":"573","author":"AG Solis","year":"2019","unstructured":"Solis, A. G. et al. Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity. Nature 573, 69\u201374 (2019).","journal-title":"Nature"},{"key":"1616_CR65","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1016\/j.cell.2020.06.022","volume":"182","author":"E Sugisawa","year":"2020","unstructured":"Sugisawa, E. et al. RNA sensing by gut Piezo1 is essential for systemic serotonin synthesis. Cell 182, 609\u2013624.e21 (2020).","journal-title":"Cell"},{"key":"1616_CR66","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.yjmcc.2021.05.002","volume":"158","author":"D Jakob","year":"2021","unstructured":"Jakob, D. et al. Piezo1 and BKCa channels in human atrial fibroblasts: Interplay and remodelling in atrial fibrillation. J. Mol. Cell. Cardiol. 158, 49\u201362 (2021).","journal-title":"J. Mol. Cell. Cardiol."},{"key":"1616_CR67","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.3390\/cells11071199","volume":"11","author":"F Bartoli","year":"2022","unstructured":"Bartoli, F. et al. Global PIEZO1 gain-of-function mutation causes cardiac hypertrophy and fibrosis in mice. Cells 11, 1199 (2022).","journal-title":"Cells"},{"key":"1616_CR68","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1016\/j.cardiores.2005.08.002","volume":"69","author":"AC Newby","year":"2006","unstructured":"Newby, A. C. Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates. Cardiovasc. Res. 69, 614\u2013624 (2006).","journal-title":"Cardiovasc. Res."},{"key":"1616_CR69","doi-asserted-by":"publisher","first-page":"eadp4726","DOI":"10.1126\/sciadv.adp4726","volume":"10","author":"M Ezzo","year":"2024","unstructured":"Ezzo, M. et al. Acute contact with profibrotic macrophages mechanically activates fibroblasts via \u03b1v\u03b23 integrin\u2013mediated engagement of Piezo1. Sci. Adv. 10, eadp4726 (2024).","journal-title":"Sci. Adv."},{"key":"1616_CR70","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1038\/s41421-022-00427-w","volume":"8","author":"L Niu","year":"2022","unstructured":"Niu, L. et al. A positive mechanobiological feedback loop controls bistable switching of cardiac fibroblast phenotype. Cell Discov 8, 84 (2022).","journal-title":"Cell Discov"},{"key":"1616_CR71","doi-asserted-by":"publisher","first-page":"16124","DOI":"10.1073\/pnas.1412740111","volume":"111","author":"NR Blumenthal","year":"2014","unstructured":"Blumenthal, N. R. et al. Stochastic nanoroughness modulates neuron\u2013astrocyte interactions and function via mechanosensing cation channels. Proc. Natl Acad. Sci. USA 111, 16124\u201316129 (2014).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1616_CR72","doi-asserted-by":"publisher","first-page":"e07369","DOI":"10.7554\/eLife.07369","volume":"4","author":"R Syeda","year":"2015","unstructured":"Syeda, R. et al. Chemical activation of the mechanotransduction channel Piezo1. eLife 4, e07369 (2015).","journal-title":"eLife"},{"key":"1616_CR73","doi-asserted-by":"publisher","first-page":"103610","DOI":"10.1016\/j.drudis.2023.103610","volume":"28","author":"P Young","year":"2023","unstructured":"Young, P. Treatment to cure: advancing AAV gene therapy manufacture. Drug Discov. Today 28, 103610 (2023).","journal-title":"Drug Discov. Today"},{"key":"1616_CR74","doi-asserted-by":"publisher","first-page":"1248056","DOI":"10.3389\/fimmu.2023.1248056","volume":"14","author":"Q Cao","year":"2023","unstructured":"Cao, Q. et al. Low-intensity pulsed ultrasound of different intensities differently affects myocardial ischemia\/reperfusion injury by modulating cardiac oxidative stress and inflammatory reaction. Front. Immunol. 14, 1248056 (2023).","journal-title":"Front. Immunol."},{"key":"1616_CR75","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1186\/s12951-023-01853-y","volume":"21","author":"F Zhang","year":"2023","unstructured":"Zhang, F. et al. Combination therapy with ultrasound and 2D nanomaterials promotes recovery after spinal cord injury via Piezo1 downregulation. J. Nanobiotechnol. 21, 91 (2023).","journal-title":"J. Nanobiotechnol."},{"key":"1616_CR76","doi-asserted-by":"publisher","first-page":"665","DOI":"10.3390\/medicina59040665","volume":"59","author":"S Kusuhara","year":"2023","unstructured":"Kusuhara, S. et al. Short-term outcomes of intravitreal faricimab injection for diabetic macular edema. Medicina 59, 665 (2023).","journal-title":"Medicina"}],"container-title":["Experimental &amp; Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s12276-025-01616-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s12276-025-01616-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s12276-025-01616-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T06:06:03Z","timestamp":1774418763000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s12276-025-01616-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,9]]},"references-count":76,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["1616"],"URL":"https:\/\/doi.org\/10.1038\/s12276-025-01616-9","relation":{},"ISSN":["2092-6413"],"issn-type":[{"value":"2092-6413","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,9]]},"assertion":[{"value":"12 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 September 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 October 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 January 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}