{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T18:02:37Z","timestamp":1789408957839,"version":"build-2803163510"},"reference-count":72,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003981","name":"Agenzia Spaziale Italiana","doi-asserted-by":"publisher","award":["2021-21-U.O. ASTRONEMUS"],"award-info":[{"award-number":["2021-21-U.O. ASTRONEMUS"]}],"id":[{"id":"10.13039\/501100003981","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2021-21-U.O. ASTRONEMUS"],"award-info":[{"award-number":["2021-21-U.O. ASTRONEMUS"]}],"id":[{"id":"https:\/\/ror.org\/034zgem50","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Background: Facioscapulohumeral muscular dystrophy (FSHD) is a progressive and heterogeneous disorder lacking reliable circulating biomarkers for disease monitoring and therapeutic response. We hypothesized that metabolic dysregulation, lipotoxicity, and endoplasmic reticulum (ER) stress induce sphingolipid remodeling that is reflected in serum and correlates with disease severity. Methods: We performed RNA sequencing, differential expression, and pathway analyses on biceps brachii muscle biopsies from mild (n = 9) and severe (n = 5) FSHD patients and healthy controls (n = 6). Selected transcripts were validated by OpenArray quantitative PCR. Serum samples from mild (n = 9), severe (n = 13), and control subjects (n = 10) were analyzed by targeted and untargeted LC-MS\/MS sphingolipidomics. Results: Severe FSHD exhibited transcriptomic signatures of mitochondrial dysfunction, ER stress, inflammation, and extracellular vesicle biogenesis. RNA-seq revealed activation of the de novo ceramide synthesis pathway, with increased SPTLC1\u20133, CERS2, CERS5, and DEGS1, reduced SMPD1\/4 and SMPDL3A, and dysregulation of cerebroside metabolism. Migrasome\/extracellular vesicle markers (TSPAN4, TM4SF1, PIGK, CPQ, ITGA5, and ITGB1) were predominantly upregulated in patients with severe disease. Serum lipidomics showed severity-dependent increases in dihydroceramides, ceramides, sphingomyelins, and dihydrosphingomyelins, while the Cer\/HexCer d18:1\/18:0 ratio progressively increased with disease severity. Conclusions: Integrated transcriptomic and lipidomic analyses identify sphingolipid dysregulation and extracellular vesicle biogenesis as hallmarks of severe FSHD and support circulating sphingolipids as candidate biomarkers for disease severity and therapeutic monitoring.<\/jats:p>","DOI":"10.3390\/antiox15091166","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T17:01:00Z","timestamp":1789405260000},"page":"1166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sphingolipid Remodeling and Extracellular Vesicle Signatures Reflect Disease Severity in Facioscapulohumeral Dystrophy Driven by Mitochondrial Dysfunction and Endoplasmic Reticulum Stress"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4718-0307","authenticated-orcid":false,"given":"Manuela","family":"Moriggi","sequence":"first","affiliation":[{"name":"Laboratory of Proteomics and Lipidomics, IRCCS Galeazzi-Sant\u2019Ambrogio Hospital, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Lucia","family":"Ruggiero","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6374-3325","authenticated-orcid":false,"given":"Enrica","family":"Torretta","sequence":"additional","affiliation":[{"name":"Laboratory of Proteomics and Lipidomics, IRCCS Galeazzi-Sant\u2019Ambrogio Hospital, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Dario","family":"Zoppi","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0615-3580","authenticated-orcid":false,"given":"Beatrice","family":"Arosio","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"}]},{"given":"Chiara","family":"Fiorillo","sequence":"additional","affiliation":[{"name":"Child Neuropsychiatryc Unit, IRCCS Istituto Giannina Gaslini, DINOGMI-University of Genova, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"given":"Vincenzo","family":"Nigro","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7701-728X","authenticated-orcid":false,"given":"Daniele","family":"Capitanio","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2996-6912","authenticated-orcid":false,"given":"Cecilia","family":"Gelfi","sequence":"additional","affiliation":[{"name":"Laboratory of Proteomics and Lipidomics, IRCCS Galeazzi-Sant\u2019Ambrogio Hospital, 20157 Milan, Italy"},{"name":"Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"ref_1","first-page":"1650","article-title":"A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy","volume":"329","author":"Lemmers","year":"2010","journal-title":"Science (1979)"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1007\/s00415-019-09242-y","article-title":"Relationship between Muscle Inflammation and Fat Replacement Assessed by MRI in Facioscapulohumeral Muscular Dystrophy","volume":"266","author":"Dahlqvist","year":"2019","journal-title":"J. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Tasca, G., Pescatori, M., Monforte, M., Mirabella, M., Iannaccone, E., Frusciante, R., Cubeddu, T., Laschena, F., Ottaviani, P., and Ricci, E. (2012). Different Molecular Signatures in Magnetic Resonance Imaging-Staged Facioscapulohumeral Muscular Dystrophy Muscles. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038779"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.2174\/1566524014666141010155054","article-title":"Facioscapulohumeral Muscular Dystrophy: More Complex than It Appears","volume":"14","author":"Ricci","year":"2014","journal-title":"Curr. Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e204040","DOI":"10.1001\/jamanetworkopen.2020.4040","article-title":"Phenotypic Variability Among Patients With D4Z4 Reduced Allele Facioscapulohumeral Muscular Dystrophy","volume":"3","author":"Ruggiero","year":"2020","journal-title":"JAMA Netw. Open"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41582-022-00762-2","article-title":"Facioscapulohumeral Muscular Dystrophy: The Road to Targeted Therapies","volume":"19","author":"Tihaya","year":"2023","journal-title":"Nat. Rev. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Moriggi, M., Ruggiero, L., Torretta, E., Zoppi, D., Arosio, B., Ferri, E., Castegna, A., Fiorillo, C., Gelfi, C., and Capitanio, D. (2024). Muscle Proteome Analysis of Facioscapulohumeral Dystrophy Patients Reveals a Metabolic Rewiring Promoting Oxidative\/Reductive Stress Contributing to the Loss of Muscle Function. Antioxidants, 13.","DOI":"10.3390\/antiox13111406"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"17547","DOI":"10.1038\/s41598-020-74687-5","article-title":"Evaluation of Blood Gene Expression Levels in Facioscapulohumeral Muscular Dystrophy Patients","volume":"10","author":"Signorelli","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"EMMM202013695","DOI":"10.15252\/emmm.202013695","article-title":"Pathomechanisms and Biomarkers in Facioscapulohumeral Muscular Dystrophy: Roles of DUX4 and PAX7","volume":"13","author":"Banerji","year":"2021","journal-title":"EMBO Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Heier, C., Zhang, A., Nguyen, N., Tully, C., Panigrahi, A., Gordish-Dressman, H., Pandey, S., Guglieri, M., Ryan, M., and Clemens, P. (2020). Multi-Omics Identifies Circulating MiRNA and Protein Biomarkers for Facioscapulohumeral Dystrophy. J. Pers. Med., 10.","DOI":"10.3390\/jpm10040236"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Corasolla Carregari, V., Monforte, M., Di Maio, G., Pieroni, L., Urbani, A., Ricci, E., and Tasca, G. (2020). Proteomics of Muscle Microdialysates Identifies Potential Circulating Biomarkers in Facioscapulohumeral Muscular Dystrophy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010290"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"83","DOI":"10.3233\/JND-210711","article-title":"Identification of Serum Interleukin 6 Levels as a Disease Severity Biomarker in Facioscapulohumeral Muscular Dystrophy","volume":"9","author":"Gros","year":"2022","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"327","DOI":"10.3233\/JND-230063","article-title":"IL-6 and TNF Are Potential Inflammatory Biomarkers in Facioscapulohumeral Muscular Dystrophy","volume":"11","author":"Greco","year":"2024","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1093\/hmg\/ddab364","article-title":"Elevated Plasma Complement Components in Facioscapulohumeral Dystrophy","volume":"31","author":"Wong","year":"2022","journal-title":"Hum. Mol. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16664","DOI":"10.1038\/s41598-019-53122-4","article-title":"Sphingolipid Serum Profiling in Vitamin D Deficient and Dyslipidemic Obese Dimorphic Adults","volume":"9","author":"Torretta","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Barbacini, P., Torretta, E., Arosio, B., Ferri, E., Capitanio, D., Moriggi, M., and Gelfi, C. (2022). Novel Insight into the Serum Sphingolipid Fingerprint Characterizing Longevity. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052428"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1038\/s42255-019-0134-8","article-title":"Metabolic Messengers: Ceramides","volume":"1","author":"Summers","year":"2019","journal-title":"Nat. Metab."},{"key":"ref_18","first-page":"386","article-title":"Targeting a Ceramide Double Bond Improves Insulin Resistance and Hepatic Steatosis","volume":"365","author":"Chaurasia","year":"2019","journal-title":"Science (1979)"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1038\/s41574-020-0320-5","article-title":"The Role of Ceramides in Metabolic Disorders: When Size and Localization Matters","volume":"16","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1016\/j.cell.2019.05.008","article-title":"CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondrial Fragmentation in Obesity","volume":"177","author":"Hammerschmidt","year":"2019","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/j.cmet.2021.06.006","article-title":"Sphingolipids in Metabolic Disease: The Good, the Bad, and the Unknown","volume":"33","author":"Green","year":"2021","journal-title":"Cell Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1038\/s43587-022-00309-6","article-title":"Sphingolipids Accumulate in Aged Muscle, and Their Reduction Counteracts Sarcopenia","volume":"2","author":"Laurila","year":"2022","journal-title":"Nat. Aging"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"eade6509","DOI":"10.1126\/scitranslmed.ade6509","article-title":"Inhibiting de Novo Ceramide Synthesis Restores Mitochondrial and Protein Homeostasis in Muscle Aging","volume":"15","author":"Lima","year":"2023","journal-title":"Sci. Transl. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1002\/jcsm.12473","article-title":"Tracking Muscle Wasting and Disease Activity in Facioscapulohumeral Muscular Dystrophy by Qualitative Longitudinal Imaging","volume":"10","author":"Monforte","year":"2019","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1002\/jcsm.13250","article-title":"Five-year Follow-up Study on Quantitative Muscle Magnetic Resonance Imaging in Facioscapulohumeral Muscular Dystrophy: The Link to Clinical Outcome","volume":"14","author":"Vincenten","year":"2023","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2604","DOI":"10.1111\/ene.14446","article-title":"Deep Phenotyping of Facioscapulohumeral Muscular Dystrophy Type 2 by Magnetic Resonance Imaging","volume":"27","author":"Giacomucci","year":"2020","journal-title":"Eur. J. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"15462","DOI":"10.1038\/s41598-024-65802-x","article-title":"AI Driven Analysis of MRI to Measure Health and Disease Progression in FSHD","volume":"14","author":"Riem","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/mus.21671","article-title":"A Standardized Clinical Evaluation of Patients Affected by Facioscapulohumeral Muscular Dystrophy: The FSHD Clinical Score","volume":"42","author":"Lamperti","year":"2010","journal-title":"Muscle Nerve"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.freeradbiomed.2024.04.001","article-title":"Muscle Strength, Quantity and Quality and Muscle Fat Quantity and Their Association with Oxidative Stress in Patients with Facioscapulohumeral Muscular Dystrophy: Effect of Antioxidant Supplementation","volume":"219","author":"Wilson","year":"2024","journal-title":"Free Radic. Biol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor Package for Differential Expression Analysis of Digital Gene Expression Data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"R80","DOI":"10.1186\/gb-2004-5-10-r80","article-title":"Bioconductor: Open Software Development for Computational Biology and Bioinformatics","volume":"5","author":"Gentleman","year":"2004","journal-title":"Genome Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1093\/hmg\/ddt468","article-title":"Neuronal Accumulation of Glucosylceramide in a Mouse Model of Neuronopathic Gaucher Disease Leads to Neurodegeneration","volume":"23","author":"Vitner","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s13024-024-00713-z","article-title":"GBA1 Inactivation in Oligodendrocytes Affects Myelination and Induces Neurodegenerative Hallmarks and Lipid Dyshomeostasis in Mice","volume":"19","author":"Gregorio","year":"2024","journal-title":"Mol. Neurodegener."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1074\/jbc.M116.762831","article-title":"Identification of a Feedback Loop Involving \u03b2-Glucosidase 2 and Its Product Sphingosine Sheds Light on the Molecular Mechanisms in Gaucher Disease","volume":"292","author":"Schonauer","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_35","first-page":"567","article-title":"Isolation of \u03b2-Galactosidase and \u03b2-Glucosidase from Brain","volume":"113","author":"Gatt","year":"1966","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Enzymol. Biol. Oxid."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4633","DOI":"10.1007\/s10072-025-08276-7","article-title":"Describing Phenotypes in FSHD: An Update of the Comprehensive Clinical Evaluation Form","volume":"46","author":"Ricci","year":"2025","journal-title":"Neurol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/S1474-4422(24)00073-5","article-title":"Safety and Efficacy of Losmapimod in Facioscapulohumeral Muscular Dystrophy (ReDUX4): A Randomised, Double-Blind, Placebo-Controlled Phase 2b Trial","volume":"23","author":"Tawil","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"LoRusso, S., Johnson, N.E., McDermott, M.P., Eichinger, K., Butterfield, R.J., Carraro, E., Higgs, K., Lewis, L., Mul, K., and Sacconi, S. (2019). Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD (ReSolve): Protocol of a Large, International, Multi-Center Prospective Study. BMC Neurol., 19.","DOI":"10.1186\/s12883-019-1452-x"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Vainshtein, A., Blaauw, B., De Bock, K., Munoz-Canoves, P., Olson, E.N., Ottenheijm, C.A.C., Richter, E.A., Ruas, J.L., Schaffer, L., and Spiegelman, B. (2026). The Hallmarks of Skeletal Muscle Health. Nat. Metab.","DOI":"10.1038\/s42255-026-01595-9"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1038\/s41467-022-29363-9","article-title":"Long-Chain Ceramides Are Cell Non-Autonomous Signals Linking Lipotoxicity to Endoplasmic Reticulum Stress in Skeletal Muscle","volume":"13","author":"McNally","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/S0047-6374(01)00246-9","article-title":"Sphingomyelin and Ceramide as Regulators of Development and Lifespan","volume":"122","author":"Cutler","year":"2001","journal-title":"Mech. Ageing Dev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1006\/abbi.1997.0113","article-title":"Effect of Butylhydroxytoluene and Related Compounds on Permeability of the Inner Mitochondrial Membrane","volume":"342","author":"Gudz","year":"1997","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"20296","DOI":"10.1074\/jbc.274.29.20296","article-title":"Ceramide Induces Bcl2 Dephosphorylation via a Mechanism Involving Mitochondrial PP2A","volume":"274","author":"Ruvolo","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1038\/s41556-022-00934-8","article-title":"Ceramide-Rich Microdomains Facilitate Nuclear Envelope Budding for Non-Conventional Exosome Formation","volume":"24","author":"Arya","year":"2022","journal-title":"Nat. Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1111\/imr.13103","article-title":"The Expanding Family of Neutrophil-derived Extracellular Vesicles","volume":"312","author":"Marki","year":"2022","journal-title":"Immunol. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3672","DOI":"10.1111\/jcmm.17942","article-title":"Differences between Migrasome, a \u2018New Organelle\u2019, and Exosome","volume":"27","author":"Xu","year":"2023","journal-title":"J. Cell. Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e202402060","DOI":"10.1083\/jcb.202402060","article-title":"Calcium Ions Promote Migrasome Formation via Synaptotagmin-1","volume":"223","author":"Han","year":"2024","journal-title":"J. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s40364-026-00904-4","article-title":"Migrasomes: A Journey from Biogenesis to Multifaceted Roles in Health and Disease","volume":"14","author":"Zhao","year":"2026","journal-title":"Biomark. Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Torretta, E., Barbacini, P., Al-Daghri, N.M., and Gelfi, C. (2019). Sphingolipids in Obesity and Correlated Co-Morbidities: The Contribution of Gender, Age and Environment. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20235901"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2476","DOI":"10.1002\/jcsm.13582","article-title":"Sphingolipid Metabolites as Potential Circulating Biomarkers for Sarcopenia in Men","volume":"15","author":"Seo","year":"2024","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Barbacini, P., Blottner, D., Capitanio, D., Trautmann, G., Block, K., Torretta, E., Moriggi, M., Salanova, M., and Gelfi, C. (2022). Effects of Omega-3 and Antioxidant Cocktail Supplement on Prolonged Bed Rest: Results from Serum Proteome and Sphingolipids Analysis. Cells, 11.","DOI":"10.3390\/cells11132120"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"7390","DOI":"10.1093\/hmg\/ddv439","article-title":"Amyotrophic Lateral Sclerosis and Denervation Alter Sphingolipids and Up-Regulate Glucosylceramide Synthase","volume":"24","author":"Henriques","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Moriggi, M., Capitanio, D., Torretta, E., Metatla, I., Frings-Meuthen, P., Heinz, V., Trautmann, G., Salanova, M., Blottner, D., and Gelfi, C. (2026). ProteographTM-Based Proteome and Sphingolipidome Analyses Identified Novel Serum Biomarkers to Monitor Astronauts\u2019 Health in Spaceflight. Front. Physiol., 17.","DOI":"10.3389\/fphys.2026.1773221"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1093\/eurheartj\/ehw148","article-title":"Plasma Ceramides Predict Cardiovascular Death in Patients with Stable Coronary Artery Disease and Acute Coronary Syndromes beyond LDL-Cholesterol","volume":"37","author":"Laaksonen","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"100127","DOI":"10.1016\/j.jlr.2021.100127","article-title":"Clinical Lipidomics: Realizing the Potential of Lipid Profiling","volume":"62","author":"Meikle","year":"2021","journal-title":"J. Lipid Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"E45","DOI":"10.1210\/jc.2013-2559","article-title":"Molecular Lipids Identify Cardiovascular Risk and Are Efficiently Lowered by Simvastatin and PCSK9 Deficiency","volume":"99","author":"Tarasov","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.chembiol.2018.10.008","article-title":"High-Throughput Plasma Lipidomics: Detailed Mapping of the Associations with Cardiometabolic Risk Factors","volume":"26","author":"Huynh","year":"2019","journal-title":"Cell Chem. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"eabh4423","DOI":"10.1126\/sciadv.abh4423","article-title":"Inhibition of Sphingolipid de Novo Synthesis Counteracts Muscular Dystrophy","volume":"8","author":"Laurila","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1080\/15548627.2021.1943177","article-title":"The Spectrum of Neurodevelopmental, Neuromuscular and Neurodegenerative Disorders Due to Defective Autophagy","volume":"18","author":"Deneubourg","year":"2022","journal-title":"Autophagy"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/cr.2014.135","article-title":"Discovery of the Migrasome, an Organelle Mediating Release of Cytoplasmic Contents during Cell Migration","volume":"25","author":"Ma","year":"2015","journal-title":"Cell Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2896","DOI":"10.1016\/j.cell.2021.04.027","article-title":"Mitocytosis, a Migrasome-Mediated Mitochondrial Quality-Control Process","volume":"184","author":"Jiao","year":"2021","journal-title":"Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/s41419-025-07943-z","article-title":"Biogenesis, Functional Roles, and Pathological Implications of Migrasomes","volume":"16","author":"Liu","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1038\/s41556-023-01188-8","article-title":"The Formation of Migrasomes Is Initiated by the Assembly of Sphingomyelin Synthase 2 Foci at the Leading Edge of Migrating Cells","volume":"25","author":"Liang","year":"2023","journal-title":"Nat. Cell Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3762","DOI":"10.1529\/biophysj.105.071506","article-title":"Viscoelastic Retraction of Single Living Stress Fibers and Its Impact on Cell Shape, Cytoskeletal Organization, and Extracellular Matrix Mechanics","volume":"90","author":"Kumar","year":"2006","journal-title":"Biophys. J."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Zhang, C., Zheng, M., Bai, R., Chen, J., Yang, H., and Luo, G. (2024). Molecular Mechanisms of Lipid Droplets-Mitochondria Coupling in Obesity and Metabolic Syndrome: Insights and Pharmacological Implications. Front. Physiol., 15.","DOI":"10.3389\/fphys.2024.1491815"},{"key":"ref_66","first-page":"159350","article-title":"GM1 Oligosaccharide Efficacy against \u03b1-Synuclein Aggregation and Toxicity in Vitro","volume":"1868","author":"Fazzari","year":"2023","journal-title":"Biochim. Biophys. Acta (BBA) \u2014Mol. Cell Biol. Lipids"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e194687","DOI":"10.1172\/JCI194687","article-title":"Inhibition of Ceramide Synthesis Ameliorates Body Wasting in a Cancer Cachexia Model","volume":"136","author":"Morigny","year":"2026","journal-title":"J. Clin. Investig."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Fazzari, M., Lunghi, G., Henriques, A., Callizot, N., Ciampa, M.G., Mauri, L., Prioni, S., Carsana, E.V., Loberto, N., and Aureli, M. (2023). GM1 Oligosaccharide Efficacy in Parkinson\u2019s Disease: Protection against MPTP. Biomedicines, 11.","DOI":"10.3390\/biomedicines11051305"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.freeradbiomed.2026.02.071","article-title":"Personalized Antioxidant Supplementation Improves Muscle Strength, Physical Activity, and Quality of Life in Patients with FSHD1: A Real-World Longitudinal Study","volume":"248","author":"Arbogast","year":"2026","journal-title":"Free Radic. Biol. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.aca.2017.04.008","article-title":"Workflow Development for Targeted Lipidomic Quantification Using Parallel Reaction Monitoring on a Quadrupole-Time of Flight Mass Spectrometry","volume":"972","author":"Zhou","year":"2017","journal-title":"Anal. Chim. Acta"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1194\/jlr.D119000393","article-title":"Shared Reference Materials Harmonize Lipidomics across MS-Based Detection Platforms and Laboratories","volume":"61","author":"Triebl","year":"2020","journal-title":"J. Lipid Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1093\/hmg\/ddad175","article-title":"FSHD Muscle Shows Perturbation in Fibroadipogenic Progenitor Cells, Mitochondrial Function and Alternative Splicing Independently of Inflammation","volume":"33","author":"Engquist","year":"2024","journal-title":"Hum. Mol. Genet."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/9\/1166\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T17:03:46Z","timestamp":1789405426000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/9\/1166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,14]]},"references-count":72,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["antiox15091166"],"URL":"https:\/\/doi.org\/10.3390\/antiox15091166","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,14]]}}}