{"id":"https://openalex.org/W7214344980","doi":"https://doi.org/10.64898/2026.09.21.753166","title":"Calcium dysregulation amplifies fibrotic responses to TGF\u03b2 in human Friedreich\u2019s ataxia fibroblasts","display_name":"Calcium dysregulation amplifies fibrotic responses to TGF\u03b2 in human Friedreich\u2019s ataxia fibroblasts","publication_year":2026,"publication_date":"2026-09-25","ids":{"openalex":"https://openalex.org/W7214344980","doi":"https://doi.org/10.64898/2026.09.21.753166","pmid":"https://pubmed.ncbi.nlm.nih.gov/42818031","pmcid":"https://www.ncbi.nlm.nih.gov/pmc/articles/13622188"},"language":"en","primary_location":{"id":"doi:10.64898/2026.09.21.753166","doi":"https://doi.org/10.64898/2026.09.21.753166","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.09.21.753166","pdf_url":"https://www.biorxiv.org/content/biorxiv/early/2026/09/25/2026.09.21.753166.full.pdf","source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by-nc-nd","license_id":"https://openalex.org/licenses/cc-by-nc-nd","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"},"volume":null,"type":"preprint","is_traditional":true,"indexed_in":["crossref","pubmed"],"open_access":{"is_oa":true,"oa_status":"green","oa_url":"https://www.biorxiv.org/content/biorxiv/early/2026/09/25/2026.09.21.753166.full.pdf","any_repository_has_fulltext":true},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5076294686","display_name":"\u0410\u043d\u043d\u0430 \u0421\u0442\u0435\u043f\u0430\u043d\u043e\u0432\u0430","orcid":"https://orcid.org/0000-0001-6557-0539","observed_orcids":["https://orcid.org/0000-0001-6557-0539"]},"institutions":[{"id":"https://openalex.org/I4387153466","display_name":"Weill Cornell Medicine","ror":"https://ror.org/02r109517","country_code":"US","type":"education","lineage":["https://openalex.org/I205783295","https://openalex.org/I4387153466"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Anna Stepanova","raw_affiliation_strings":["Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA"],"raw_orcid":"https://orcid.org/0000-0001-6557-0539","affiliations":[{"raw_affiliation_string":"Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA","institution_ids":["https://openalex.org/I4387153466"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5021244706","display_name":"Hibiki Kawamata","orcid":"https://orcid.org/0000-0003-0020-6933","observed_orcids":["https://orcid.org/0000-0003-0020-6933"]},"institutions":[{"id":"https://openalex.org/I4387153466","display_name":"Weill Cornell Medicine","ror":"https://ror.org/02r109517","country_code":"US","type":"education","lineage":["https://openalex.org/I205783295","https://openalex.org/I4387153466"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Hibiki Kawamata","raw_affiliation_strings":["Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA"],"raw_orcid":"https://orcid.org/0000-0003-0020-6933","affiliations":[{"raw_affiliation_string":"Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA","institution_ids":["https://openalex.org/I4387153466"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5068204379","display_name":"Giovanni Manfredi","orcid":"https://orcid.org/0000-0003-3893-1348","observed_orcids":["https://orcid.org/0000-0003-3893-1348"]},"institutions":[{"id":"https://openalex.org/I4387153466","display_name":"Weill Cornell Medicine","ror":"https://ror.org/02r109517","country_code":"US","type":"education","lineage":["https://openalex.org/I205783295","https://openalex.org/I4387153466"]}],"countries":["US"],"is_corresponding":true,"raw_author_name":"Giovanni Manfredi","raw_affiliation_strings":["Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA"],"raw_orcid":"https://orcid.org/0000-0003-3893-1348","affiliations":[{"raw_affiliation_string":"Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA","institution_ids":["https://openalex.org/I4387153466"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":1,"corresponding_author_ids":["https://openalex.org/A5068204379"],"corresponding_institution_ids":["https://openalex.org/I4387153466"],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":true,"cited_by_count":0,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T11962","display_name":"Cardiac Fibrosis and Remodeling","score":0.8179000020027161,"subfield":{"id":"https://openalex.org/subfields/2705","display_name":"Cardiology and Cardiovascular Medicine"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},"topics":[{"id":"https://openalex.org/T11962","display_name":"Cardiac Fibrosis and Remodeling","score":0.8179000020027161,"subfield":{"id":"https://openalex.org/subfields/2705","display_name":"Cardiology and Cardiovascular Medicine"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T10217","display_name":"Cardiac electrophysiology and arrhythmias","score":0.05180000141263008,"subfield":{"id":"https://openalex.org/subfields/2705","display_name":"Cardiology and Cardiovascular Medicine"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T12620","display_name":"Signaling Pathways in Disease","score":0.03400000184774399,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/friedreich-ataxia","display_name":"Friedreich's ataxia","score":0.9990000128746033},{"id":"https://openalex.org/keywords/frataxin","display_name":"frataxin","score":0.9459999799728394},{"id":"https://openalex.org/keywords/myocardial-fibrosis","display_name":"myocardial fibrosis","score":0.8820000290870667},{"id":"https://openalex.org/keywords/myofibroblast-differentiation","display_name":"myofibroblast differentiation","score":0.8870000243186951},{"id":"https://openalex.org/keywords/tgf-beta-signaling","display_name":"TGF-beta signaling","score":0.656000018119812},{"id":"https://openalex.org/keywords/nfat-transcription-factors","display_name":"NFAT transcription factors","score":0.8069999814033508},{"id":"https://openalex.org/keywords/connective-tissue-growth-factor","display_name":"connective tissue growth factor","score":0.9409999847412109},{"id":"https://openalex.org/keywords/ccn3","display_name":"CCN3","score":0.9269999861717224},{"id":"https://openalex.org/keywords/nox4","display_name":"NOX4","score":0.9610000252723694},{"id":"https://openalex.org/keywords/fibroblast-reprogramming","display_name":"fibroblast reprogramming","score":0.7149999737739563},{"id":"https://openalex.org/keywords/cardiomyopathy","display_name":"cardiomyopathy","score":0.8240000009536743}],"concepts":[{"id":"https://openalex.org/C2780559512","wikidata":"https://www.wikidata.org/wiki/Q605709","display_name":"Fibrosis","level":2,"score":0.6313999891281128},{"id":"https://openalex.org/C207865475","wikidata":"https://www.wikidata.org/wiki/Q1467330","display_name":"Myofibroblast","level":3,"score":0.5562999844551086},{"id":"https://openalex.org/C2776925932","wikidata":"https://www.wikidata.org/wiki/Q1755122","display_name":"Neurodegeneration","level":3,"score":0.5174999833106995},{"id":"https://openalex.org/C134018914","wikidata":"https://www.wikidata.org/wiki/Q162606","display_name":"Endocrinology","level":1,"score":0.515999972820282},{"id":"https://openalex.org/C2777735026","wikidata":"https://www.wikidata.org/wiki/Q24724654","display_name":"Sodium-calcium exchanger","level":3,"score":0.4986000061035156},{"id":"https://openalex.org/C126322002","wikidata":"https://www.wikidata.org/wiki/Q11180","display_name":"Internal medicine","level":1,"score":0.47749999165534973},{"id":"https://openalex.org/C2780381497","wikidata":"https://www.wikidata.org/wiki/Q463418","display_name":"Fibroblast","level":3,"score":0.4586000144481659},{"id":"https://openalex.org/C77255625","wikidata":"https://www.wikidata.org/wiki/Q402093","display_name":"Reprogramming","level":3,"score":0.45170000195503235},{"id":"https://openalex.org/C2780906641","wikidata":"https://www.wikidata.org/wiki/Q213373","display_name":"Ataxia","level":2,"score":0.4489000141620636},{"id":"https://openalex.org/C519063684","wikidata":"https://www.wikidata.org/wiki/Q706","display_name":"Calcium","level":2,"score":0.42719998955726624},{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.42010000348091125},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.4083999991416931},{"id":"https://openalex.org/C150194340","wikidata":"https://www.wikidata.org/wiki/Q26972","display_name":"Gene expression","level":3,"score":0.3716999888420105},{"id":"https://openalex.org/C62478195","wikidata":"https://www.wikidata.org/wiki/Q828130","display_name":"Signal transduction","level":2,"score":0.3646000027656555},{"id":"https://openalex.org/C95444343","wikidata":"https://www.wikidata.org/wiki/Q7141","display_name":"Cell biology","level":1,"score":0.3571000099182129},{"id":"https://openalex.org/C127561419","wikidata":"https://www.wikidata.org/wiki/Q224527","display_name":"Downregulation and upregulation","level":3,"score":0.3529999852180481},{"id":"https://openalex.org/C2777420927","wikidata":"https://www.wikidata.org/wiki/Q5038318","display_name":"Cardiac fibrosis","level":3,"score":0.3522999882698059},{"id":"https://openalex.org/C98539663","wikidata":"https://www.wikidata.org/wiki/Q220599","display_name":"Cytosol","level":3,"score":0.3458000123500824},{"id":"https://openalex.org/C86339819","wikidata":"https://www.wikidata.org/wiki/Q407384","display_name":"Transcription factor","level":3,"score":0.3357999920845032},{"id":"https://openalex.org/C87975464","wikidata":"https://www.wikidata.org/wiki/Q910704","display_name":"Calcium metabolism","level":3,"score":0.32030001282691956},{"id":"https://openalex.org/C181080969","wikidata":"https://www.wikidata.org/wiki/Q60097","display_name":"Calcium in biology","level":3,"score":0.3179999887943268},{"id":"https://openalex.org/C502942594","wikidata":"https://www.wikidata.org/wiki/Q3421914","display_name":"Cancer research","level":1,"score":0.3165999948978424},{"id":"https://openalex.org/C118131993","wikidata":"https://www.wikidata.org/wiki/Q423671","display_name":"Transforming growth factor","level":2,"score":0.3140999972820282},{"id":"https://openalex.org/C2778797674","wikidata":"https://www.wikidata.org/wiki/Q847583","display_name":"Cardiomyopathy","level":3,"score":0.28859999775886536},{"id":"https://openalex.org/C201571599","wikidata":"https://www.wikidata.org/wiki/Q5018840","display_name":"Calcium signaling","level":3,"score":0.27399998903274536},{"id":"https://openalex.org/C69053785","wikidata":"https://www.wikidata.org/wiki/Q907394","display_name":"Serum response factor","level":4,"score":0.2680000066757202},{"id":"https://openalex.org/C2779314966","wikidata":"https://www.wikidata.org/wiki/Q409999","display_name":"Frataxin","level":4,"score":0.25839999318122864},{"id":"https://openalex.org/C71924100","wikidata":"https://www.wikidata.org/wiki/Q11190","display_name":"Medicine","level":0,"score":0.2549000084400177},{"id":"https://openalex.org/C153911025","wikidata":"https://www.wikidata.org/wiki/Q7202","display_name":"Molecular biology","level":1,"score":0.25290000438690186}],"mesh":[],"locations_count":3,"locations":[{"id":"doi:10.64898/2026.09.21.753166","doi":"https://doi.org/10.64898/2026.09.21.753166","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.09.21.753166","pdf_url":"https://www.biorxiv.org/content/biorxiv/early/2026/09/25/2026.09.21.753166.full.pdf","source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by-nc-nd","license_id":"https://openalex.org/licenses/cc-by-nc-nd","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"},{"id":"pmid:42818031","doi":null,"is_oa":false,"landing_page_url":"https://pubmed.ncbi.nlm.nih.gov/42818031","pdf_url":null,"source":{"id":"https://openalex.org/S4306525036","display_name":"PubMed","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I1299303238","host_organization_name":"National Institutes of Health","host_organization_lineage":["https://openalex.org/I1299303238"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"bioRxiv : the preprint server for biology","raw_type":"Journal Article"},{"id":"pmh:oai:pubmedcentral.nih.gov:13622188","doi":null,"is_oa":true,"landing_page_url":"https://pubmed.ncbi.nlm.nih.gov/42818031/","pdf_url":null,"source":{"id":"https://openalex.org/S2764455111","display_name":"PubMed Central","issn_l":null,"issn":null,"is_oa":true,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I1299303238","host_organization_name":"National Institutes of Health","host_organization_lineage":["https://openalex.org/I1299303238"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by-nc-nd","license_id":"https://openalex.org/licenses/cc-by-nc-nd","version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"bioRxiv","raw_type":"Text"}],"best_oa_location":{"id":"doi:10.64898/2026.09.21.753166","doi":"https://doi.org/10.64898/2026.09.21.753166","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.09.21.753166","pdf_url":"https://www.biorxiv.org/content/biorxiv/early/2026/09/25/2026.09.21.753166.full.pdf","source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by-nc-nd","license_id":"https://openalex.org/licenses/cc-by-nc-nd","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"},"sustainable_development_goals":[{"score":0.9537000060081482,"id":"https://metadata.un.org/sdg/3","display_name":"Good health and well-being"}],"study_designs":[],"awards":[],"funders":[{"id":"https://openalex.org/F4320306958","display_name":"Friedreich's Ataxia Research Alliance","ror":"https://ror.org/04edgdk70"},{"id":"https://openalex.org/F4320332161","display_name":"National Institutes of Health","ror":"https://ror.org/01cwqze88"}],"has_content":{"grobid_xml":true,"pdf":true},"content_urls":{"pdf":"https://content.openalex.org/works/W7214344980.pdf","grobid_xml":"https://content.openalex.org/works/W7214344980.grobid-xml"},"referenced_works_count":0,"referenced_works":[],"related_works":["https://openalex.org/W2894702676","https://openalex.org/W4388648706","https://openalex.org/W7207355270","https://openalex.org/W7221042384","https://openalex.org/W4403246184","https://openalex.org/W4377015355","https://openalex.org/W7037848574","https://openalex.org/W4380763297","https://openalex.org/W7154795885","https://openalex.org/W6993117041"],"abstract_inverted_index":{"Abstract":[0],"Friedreich\u2019s":[1],"ataxia":[2],"(FA)":[3],"is":[4],"an":[5,175],"inherited":[6],"disease":[7],"caused":[8],"by":[9,18,28,75],"loss":[10],"of":[11,52,72,88,97,122,165,178],"frataxin":[12],"(":[13,90,99],"FXN":[14,109,131],")":[15,94,101],"and":[16,20,95,118,152,170],"characterized":[17],"neurodegeneration":[19],"fatal":[21],"cardiomyopathy.":[22],"Cardiac":[23],"fibrosis":[24,179],"contributes":[25],"to":[26],"cardiomyopathy":[27],"stiffening":[29],"the":[30,34,50,76,123],"heart":[31],"wall,":[32],"yet":[33],"underlying":[35],"mechanisms":[36],"remain":[37],"unknown.":[38],"Here,":[39],"we":[40],"investigated":[41],"pro-fibrotic":[42,63,89],"predisposition":[43],"in":[44,56,66,136,146,156,168],"FA":[45,67,83,112,140,147,169],"patient-derived":[46],"fibroblasts,":[47,68],"focusing":[48],"on":[49],"role":[51],"cytosolic":[53,116],"calcium":[54],"(Ca)":[55],"TGF\u03b2-driven":[57],"fibroblast-to-myofibroblast":[58],"transition":[59],"(FMT).":[60],"We":[61],"found":[62],"transcriptional":[64],"priming":[65],"alongside":[69],"elevated":[70,115],"expression":[71,121],"genes":[73],"controlled":[74],"Ca-responsive":[77],"transcription":[78],"factor":[79],"NFAT.":[80],"Upon":[81],"FMT,":[82],"myofibroblasts":[84],"showed":[85],"amplified":[86],"induction":[87,155],"CCN2":[91,154],",":[92],"NOX4":[93],"suppression":[96],"anti-fibrotic":[98],"CCN3":[100],"genes,":[102],"which":[103,127],"were":[104],"inversely":[105],"correlated":[106,129],"with":[107,130],"residual":[108],".":[110,132],"Mechanistically,":[111],"fibroblasts":[113,138,148],"exhibited":[114],"Ca":[117,141,150,172],"strongly":[119],"downregulated":[120],"Na-Ca":[124],"exchanger":[125],"NCX1,":[126],"directly":[128],"Furthermore,":[133],"NCX1":[134,144,161],"inhibition":[135],"control":[137],"recapitulated":[139],"phenotypes,":[142],"whereas":[143],"transduction":[145],"normalized":[149],"dynamics":[151],"blunted":[153],"FMT.":[157],"These":[158],"findings":[159],"highlight":[160],"as":[162,174],"a":[163],"modulator":[164],"fibrotic":[166],"reprogramming":[167],"identify":[171],"dyshomeostasis":[173],"intrinsic":[176],"mechanism":[177],"that":[180],"could":[181],"be":[182],"targeted":[183],"therapeutically.":[184]},"counts_by_year":[],"updated_date":"2026-11-08T12:12:28.789561","created_date":"2026-09-26T00:00:00"}
