{"doi":"10.1016/j.intimp.2025.115280","title":"S100A9 inhibition ameliorates HFpEF by modulating mitochondrial fission and oxidative stress","abstract":null,"journal":"International Immunopharmacology","year":2025,"id":644057,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1639076,"name":"Bowen Ren","orcid":null,"position":1,"is_corresponding":false},{"id":1676131,"name":"Xiaofan Wu","orcid":null,"position":2,"is_corresponding":false},{"id":1017578,"name":"Junyi Guo","orcid":null,"position":3,"is_corresponding":false},{"id":1428799,"name":"Yu Cao","orcid":"0000-0002-5661-5851","position":4,"is_corresponding":false},{"id":1676132,"name":"Lintong Men","orcid":null,"position":5,"is_corresponding":false},{"id":923727,"name":"Wei Shi","orcid":"0000-0002-2236-4708","position":6,"is_corresponding":false},{"id":990225,"name":"Cuntai Zhang","orcid":"0000-0002-2365-5646","position":7,"is_corresponding":false},{"id":309366,"name":"Li Lin","orcid":"0000-0003-3355-6139","position":8,"is_corresponding":false},{"id":1676133,"name":"Jiagao Lv","orcid":null,"position":9,"is_corresponding":false},{"id":940310,"name":"Sheng Li","orcid":"0000-0002-8901-2184","position":10,"is_corresponding":false},{"id":1676134,"name":"Shengqi Huo","orcid":null,"position":11,"is_corresponding":false},{"id":1676130,"name":"Moran Wang","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"S100A9 inhibition ameliorates HFpEF by modulating mitochondrial fission and oxidative stress","abstract":"Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction and myocardial stiffness, with limited treatment options due to the unclear molecular mechanisms underlying the disease. In this study, we investigate the role of S100A9, an inflammatory mediator, in regulating mitochondrial dynamics in HFpEF. Using “two-hit” (high-fat diet and L-NAME) and db/db mouse models, we show that S100A9 is significantly elevated in both cardiac tissue and serum, correlating with impaired diastolic function, cardiac hypertrophy, and increased oxidative stress. Inhibition of S100A9 with Paquinimod (PAQ) improved diastolic function, reduced cardiac hypertrophy, and decreased S100A9-positive macrophage infiltration, while preventing M1 macrophage polarization. In vitro, S100A9 secreted by palmitic acid-stimulated RAW 264.7 macrophages promoted mitochondrial fission in AC16 cardiomyocytes by increasing p-Drp1 and Fis1 expression, similar to the effects observed with recombinant S100A9. Excessive mitochondrial fission, regulated by S100A9, is a key factor in HFpEF progression. Transcriptomic analysis revealed significant upregulation of pyruvate dehydrogenase kinase 4 (PDK4) in HFpEF mice. Mechanistically, S100A9 induced PDK4 expression via SPI1-mediated transcription, exacerbating oxidative stress and mitochondrial fragmentation. PAQ treatment or silencing PDK4/SPI1 in AC16 cells reversed these effects, restoring ATP levels and stabilizing mitochondrial membrane potential. Cardiomyocyte-specific PDK4 knockdown in vivo further ameliorated HFpEF progression without affecting systolic function. These findings highlight S100A9 inhibition as a promising therapeutic strategy for HFpEF by targeting mitochondrial dysfunction through the S100A9/SPI1/PDK4 axis. The chart summarizes the increased expression of S100A9 in myeloid cells and its elevated levels in the circulation of HFpEF mice. S100A9 induces SPI1 expression in AC16 cells, which subsequently promotes PDK4 transcription. Upregulation of PDK4 increases p-Drp1 expression, leading to excessive mitochondrial fission and oxidative stress, which ultimately contribute to cardiac dysfunction. Inhibition of S100A9 using PAQ or knockdown of PDK4 via AAV PDK4 shRNA injection both improve cardiac and mitochondrial function in HFpEF mice. These findings suggest that activation of the S100A9/SPI1/PDK4 pathway plays a crucial role in the progression of HFpEF. • S100A9 upregulation in cardiac tissue from HFpEF murine models (“two-hit” and db/db mice). • S100A9 inhibition ameliorated cardiac remodeling, improved exercise tolerance, and excessive mitochondrial fission. • S100A9/SPI1/PDK4 axis contributes to the development of HFpEF through excessive mitochondrial fission and oxidative stress.","is_dataset_classified":null,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40714466","pmcid":null,"openalex_id":"https://openalex.org/W4412708501","authors":[],"funders":[{"funder_name":"National Natural Science Foundation of China","grant_id":"82070396","title":null},{"funder_name":"National Natural Science Foundation of China","grant_id":"81974032","title":null}],"total_grants":2,"fwci":0.79,"citation_percentile":0.74889959,"influential_citations":0,"citation_trend":[{"year":2026,"count":1}],"oa_status":"hybrid","license":"cc-by-nc-nd","oa_locations":[{"url":"https://doi.org/10.1016/j.intimp.2025.115280","host_type":"journal"},{"url":"https://doi.org/10.1016/j.intimp.2025.115280","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S1567576925012706?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S1567576925012706?httpAccept=text/plain","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40714466","host_type":"repository"}],"fields_of_study":["Cardiovascular Function and Risk Factors","S100 Proteins and Annexins","Mitochondrial Function and Pathology"],"mesh_terms":["RAW 264.7 Cells","Pyruvate Dehydrogenase Acetyl-Transferring Kinase","Animals","Disease Models, Animal","Heart Failure","Humans","Macrophages","Male","Mice, Inbred C57BL","Stroke Volume","Quinolones","Oxidative Stress","Myocytes, Cardiac","Calgranulin B","Mice","Diet, High-Fat","Mitochondrial Dynamics"],"keywords":["PDK4","S100A9","Mitochondrial fission","Oxidative stress","Heart failure with preserved ejection fraction","Cell biology","Mitochondrion","Internal medicine","Endocrinology","Medicine","Biology","Heart failure","Downregulation and upregulation","Inflammation","Ejection fraction","Biochemistry"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-08T21:45:58.425435Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}