{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:17:32Z","timestamp":1791580652688,"version":"4.3.4"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Sepsis-induced multi-organ failure involves pathological crosstalk between mitochondrial dysfunction and hyperinflammation, yet endogenous protective mechanisms remain incompletely defined. This study investigates Growth Differentiation Factor 15 (GDF15) as a potential regulator of sepsis tolerance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using LPS-challenged mouse endotoxemia and a murine macrophage (RAW264.7) cell line model, we assessed GDF15\u2019s functional role through: (1) recombinant Adeno-Associated Virus serotype 8 (rAAV8)-mediated tissue-specific overexpression, (2) siRNA knockdown, (3) pharmacological modulation (BAY 87-2243\/Hypoxia-Inducible Factor 1-alpha (HIF-1\u03b1) inhibitor, Shikonin\/PKM2 inhibitor, Asiaticoside\/SMAD7 activator), and (4) comprehensive metabolic-inflammatory phenotyping including mitochondrial complex integrity (assessed via UQCRC1, Ubiquinol-Cytochrome c Reductase Core Protein 1), cytokine dynamics (TNF-\u03b1, IL-6) and lactate metabolism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>LPS challenge induced time-dependent mitochondrial dysfunction concurrent with cytokine storms and compensatory GDF15 upregulation in both liver and macrophages. Hepatocyte-specific GDF15 overexpression attenuated injury through restored mitochondrial integrity, diminished macrophage infiltration, and reduced systemic inflammation, as evidenced by significantly lower levels of circulating TNF-\u03b1 and IL-6. Mechanistically, GDF15 preserved mitochondrial homeostasis by inducing SMAD7 expression while suppressing HIF-1\u03b1 accumulation and PKM2 nuclear translocation. Pharmacological HIF-1\u03b1\/PKM2 inhibition recapitulated GDF15\u2019s protective effects, restoring mitochondrial function and reducing inflammation even in GDF15-deficient models. Clinical analysis of a sepsis patient cohort (n=119) confirmed a significant elevation of circulating GDF15, with its levels strongly correlating with disease severity scores. Critically, SMAD7 activation attenuated HIF-1\u03b1 accumulation and rescued mitochondrial failure independently of GDF15 status.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>GDF15 orchestrates sepsis tolerance through the SMAD7-HIF-1\u03b1 axis, preserving mitochondrial integrity while resolving metabolic-inflammatory dysregulation, notably by suppressing the release of pro-inflammatory cytokines such as TNF-\u03b1 and IL-6. This study identifies GDF15 as a central guardian of mitochondrial-immune homeostasis in sepsis, positioning it as both a robust severity biomarker and a promising therapeutic target for mitochondrial resuscitation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1712741","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T06:56:19Z","timestamp":1769064979000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["GDF15 orchestrates mitochondrial-immune crosstalk via SMAD7-HIF-1\u03b1-PKM2 cascade to attenuate septic liver injury"],"prefix":"10.3389","volume":"16","author":[{"given":"Xiandong","family":"Kuang","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhili","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Central Laboratory, Renmin Hospital of Wuhan University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faxi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for sepsis and septic shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"Jama"},{"key":"B2","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s40779-022-00365-4","article-title":"Potential roles of vitamin D binding protein in attenuating liver injury in sepsis","volume":"9","author":"Xiao","year":"2022","journal-title":"Mil Med Res"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1016\/j.cell.2019.07.033","article-title":"GDF15 is an inflammation-induced central mediator of tissue tolerance","volume":"178","author":"Luan","year":"2019","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1016\/j.cmet.2017.04.021","article-title":"Age-Associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence","volume":"25","author":"Tezze","year":"2017","journal-title":"Cell Metab"},{"key":"B5","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s12974-025-03369-8","article-title":"Growth differentiation factor 15 aggravates sepsis-induced cognitive and memory impairments by promoting microglial inflammatory responses and phagocytosis","volume":"22","author":"Chen","year":"2025","journal-title":"J Neuroinflamm"},{"key":"B6","doi-asserted-by":"publisher","first-page":"115198","DOI":"10.1016\/j.intimp.2025.115198","article-title":"GDF15 attenuates sepsis-induced acute lung injury by suppressing the HIF-1\u03b1\/LDHA pathway","volume":"163","author":"Kuang","year":"2025","journal-title":"Int Immunopharmacol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"146565","DOI":"10.1016\/j.gene.2022.146565","article-title":"Effects of NRF-1 and PGC-1\u03b1 cooperation on HIF-1\u03b1 and rat cardiomyocyte apoptosis under hypoxia","volume":"834","author":"Niu","year":"2022","journal-title":"Gene"},{"key":"B8","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1038\/s41419-025-07752-4","article-title":"Oncometabolite fumarate facilitates PD-L1 expression and immune evasion in clear cell renal cell carcinoma","volume":"16","author":"Gao","year":"2025","journal-title":"Cell Death Dis"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e70555","DOI":"10.1002\/brb3.70555","article-title":"Infralimbic GABAergic may be the target of asiaticoside on alleviating bone cancer pain","volume":"15","author":"Li","year":"2025","journal-title":"Brain Behav"},{"key":"B10","doi-asserted-by":"publisher","first-page":"2562","DOI":"10.3390\/cancers14102562","article-title":"GDF15 is an eribulin response biomarker also required for survival of DTP breast cancer cells","volume":"14","author":"Bellio","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B11","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1038\/s42003-025-07834-1","article-title":"Melatonin affects trophoblast epithelial-to-mesenchymal transition and oxidative damage resistance by modulating GDF15 expression to promote embryo implantation","volume":"8","author":"Yang","year":"2025","journal-title":"Commun Biol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e31498","DOI":"10.1002\/jcp.31498","article-title":"Tumor-derived GDF15 induces tumor associated fibroblast transformation from BMSCs and fibroblasts in oral squamous cell carcinoma","volume":"240","author":"Zhao","year":"2025","journal-title":"J Cell Physiol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"5706152","DOI":"10.1155\/2017\/5706152","article-title":"Aloperine protects mice against DSS-induced colitis by PP2A-mediated PI3K\/akt\/mTOR signaling suppression","volume":"2017","author":"Fu","year":"2017","journal-title":"Mediators Inflammation"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.710977","article-title":"The clinical value of GDF15 and its prospective mechanism in sepsis","volume":"12","author":"Li","year":"2021","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00760-x","article-title":"Mitochondrial control of inflammation","volume":"23","author":"Marchi","year":"2023","journal-title":"Nat Rev Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06866-z","article-title":"A break in mitochondrial endosymbiosis as a basis for inflammatory diseases","volume":"626","author":"Murphy","year":"2024","journal-title":"Nature"},{"key":"B17","doi-asserted-by":"publisher","first-page":"11338","DOI":"10.3390\/ijms222111338","article-title":"Mitochondria as a cellular hub in infection and inflammation","volume":"22","author":"Andrieux","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-022-01094-w","article-title":"Mitochondria and cell death-associated inflammation","volume":"30","author":"Vringer","year":"2023","journal-title":"Cell Death Differ"},{"key":"B19","doi-asserted-by":"publisher","first-page":"119356","DOI":"10.1016\/j.lfs.2021.119356","article-title":"ATF4-mediated GDF15 suppresses LPS-induced inflammation and MUC5AC in human nasal epithelial cells through the PI3K\/Akt pathway","volume":"275","author":"Li","year":"2021","journal-title":"Life Sci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1101\/2025.01.30.25321437","article-title":"Mitochondrial and stress-related psychobiological regulation of FGF21 in humans","author":"Kurade","year":"2025","journal-title":"medRxiv"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1101\/2025.01.31.635929","article-title":"Mapping the GDF15 arm of the integrated stress response in human cells and tissues","author":"Smith","year":"2025","journal-title":"bioRxiv"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1101\/2025.01.28.635306","article-title":"Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging","author":"Trumpff","year":"2025","journal-title":"bioRxiv"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e12821","DOI":"10.1002\/jimd.12821","article-title":"The clinical utility in hospital-wide use of growth differentiation factor 15 as a biomarker for mitochondrial DNA-related disorders","volume":"48","author":"Fern\u00e1ndez","year":"2025","journal-title":"J Inherit Metab Dis"},{"key":"B24","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/s41398-025-03425-0","article-title":"Elevated plasma GDF15 combined with FGF21 suggests mitochondrial dysfunction in a subgroup of anorexia nervosa patients","volume":"15","author":"Xu","year":"2025","journal-title":"Transl Psychiatry"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-025-01264-3","article-title":"GDF15 links adipose tissue lipolysis with anxiety","volume":"7","author":"Townsend","year":"2025","journal-title":"Nat Metab"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2023.07.009","article-title":"GDF15 ameliorates liver fibrosis by metabolic reprogramming of macrophages to acquire anti-inflammatory properties","volume":"16","author":"Li","year":"2023","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s10330-021-0490-0","article-title":"Mechanism of tumor synthetic lethal-related targets","volume":"7","author":"Zhang","year":"2021","journal-title":"Oncol Trans Med"},{"key":"B28","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1038\/s41574-021-00529-7","article-title":"GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease","volume":"17","author":"Wang","year":"2021","journal-title":"Nat Rev Endocrinol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-021-00366-y","article-title":"Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation","volume":"3","author":"Weng","year":"2021","journal-title":"Nat Metab"},{"key":"B30","doi-asserted-by":"publisher","first-page":"111258","DOI":"10.1016\/j.celrep.2022.111258","article-title":"The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance","volume":"40","author":"Klein","year":"2022","journal-title":"Cell Rep"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.123.323360","article-title":"Fibroblast smad7 induction protects the remodeling pressure-overloaded heart","volume":"135","author":"Humeres","year":"2024","journal-title":"Circ Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2024.05.038","article-title":"PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2","volume":"32","author":"Yang","year":"2024","journal-title":"Mol Ther"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.171","article-title":"TGF-\u03b2 and NF-\u03baB signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers","volume":"32","author":"Freudlsperger","year":"2013","journal-title":"Oncogene"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00155.2013","article-title":"Hypoxia-inducible factor-2\u03b1 and TGF-\u03b2 signaling interact to promote normoxic glomerular fibrogenesis","volume":"305","author":"Hanna","year":"2013","journal-title":"Am J Physiol Renal Physiol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1007\/s10330-022-0558-8","article-title":"Metabolic reprogramming drives homeostasis and specialization of regulatory T cells in cancer","volume":"8","author":"Li","year":"2022","journal-title":"Oncol Trans Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1712741\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T06:56:21Z","timestamp":1769064981000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1712741\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,22]]},"references-count":35,"alternative-id":["10.3389\/fimmu.2025.1712741"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1712741","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,22]]},"article-number":"1712741"}}