# STAT-Mediated Mitochondrial Regulation in Cardiovascular Diseases: Mechanistic Insights and STAT3-Focused Therapeutic Strategies **Authors:** Bing Guo, Yan Fu, Min Wang, Lemei Zhu, Xuan He PMC · DOI: 10.3390/biom16020286 · Biomolecules · 2026-02-11 ## TL;DR This review explores how STAT proteins, especially STAT3, regulate mitochondria in heart and vascular diseases, and how targeting them could lead to new therapies. ## Contribution The paper provides a comprehensive review of STAT-mediated mitochondrial regulation and novel therapeutic strategies focusing on STAT3 in cardiovascular diseases. ## Key findings - STAT proteins influence mitochondrial pathways in cardiomyocytes, endothelial cells, and macrophages. - STAT3 is a key target for therapeutic strategies in mitochondrial dysfunction-related cardiovascular diseases. - Natural compounds and pharmacological inhibitors of STAT3 show promise in treating mitochondrial dysfunction. ## Abstract Mitochondria, the cell’s powerhouses, generate ATP to sustain essential biological functions. Dysfunctional mitochondria can lead to cell death and subsequent tissue damage. Mitochondrial impairment is a key driver of cellular dysfunction in cardiomyocytes, endothelial cells, and macrophages, contributing to cardiovascular diseases such as atherosclerosis, myocardial ischemia–reperfusion injury, and cardiac hypertrophy. The signal transducer and activator of transcription (STAT) family regulates immune responses, apoptosis, and cell proliferation. Despite evidence suggesting that STATs influence mitochondrial pathways in various cardiovascular conditions, their roles are often contradictory and context-dependent. This review examines the structural and functional dynamics of STATs, their upstream and downstream signaling networks, and therapeutic strategies targeting STAT3 (the most extensively studied isoform), with a particular focus on natural compounds and pharmacological inhibitors. By synthesizing current findings, this review offers valuable insights into STATs as potential therapeutic targets for mitochondrial dysfunction in cardiovascular diseases, while also highlighting directions for future research. ## Linked entities - **Genes:** STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] - **Proteins:** SOAT1 (sterol O-acyltransferase 1), STAT3 (signal transducer and activator of transcription 3) - **Diseases:** atherosclerosis (MONDO:0005311) ## Full-text entities - **Genes:** HGF (hepatocyte growth factor) [NCBI Gene 3082] {aka DFNB39, F-TCF, HGFB, HPTA, SF}, STAT1 (signal transducer and activator of transcription 1) [NCBI Gene 6772] {aka CANDF7, IMD31A, IMD31B, IMD31C, ISGF-3, STAT91}, Stat4 (signal transducer and activator of transcription 4) [NCBI Gene 367264], NOS2 (nitric oxide synthase 2) [NCBI Gene 4843] {aka HEP-NOS, INOS, NOS, NOS2A}, EGF (epidermal growth factor) [NCBI Gene 1950] {aka HOMG4, URG}, Il4 (interleukin 4) [NCBI Gene 287287] {aka Il4e12}, Ppara (peroxisome proliferator activated receptor alpha) [NCBI Gene 25747] {aka PPAR}, Hspb8 (heat shock protein family B (small) member 8) [NCBI Gene 113906] {aka Cryac, Hsp22}, Il11 (interleukin 11) [NCBI Gene 171040] {aka Il-11}, PPARGC1A (PPARG coactivator 1 alpha) [NCBI Gene 10891] {aka LEM6, PGC-1(alpha), PGC-1alpha, PGC-1v, PGC1, PGC1A}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, Stat5a (signal transducer and activator of transcription 5A) [NCBI Gene 24918] {aka Stat5}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 25125], Cxcr4 (C-X-C motif chemokine receptor 4) [NCBI Gene 60628], Stat6 (signal transducer and activator of transcription 6) [NCBI Gene 362896], Stat5b (signal transducer and activator of transcription 5B) [NCBI Gene 25126], Stat1 (signal transducer and activator of transcription 1) [NCBI Gene 20846] {aka 2010005J02Rik}, Mmp8 (matrix metallopeptidase 8) [NCBI Gene 17394], Stat2 (signal transducer and activator of transcription 2) [NCBI Gene 288774], TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, SRC (SRC proto-oncogene, non-receptor tyrosine kinase) [NCBI Gene 6714] {aka ASV, SRC1, THC6, c-SRC, p60-Src}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, CPT1A (carnitine palmitoyltransferase 1A) [NCBI Gene 1374] {aka CPT I, CPT1, CPT1-L, CPTI-L, L-CPT1}, Nppa (natriuretic peptide type A) [NCBI Gene 230899] {aka ANP, Anf, CDD, Pnd}, Mcl1 (MCL1 apoptosis regulator, BCL2 family member) [NCBI Gene 60430], ZBP1 (Z-DNA binding protein 1) [NCBI Gene 81030] {aka C20orf183, DAI, DLM-1, DLM1}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, Dnm1l (dynamin 1-like) [NCBI Gene 114114] {aka DLP1, Dnml1, Drp1}, Casp3 (caspase 3) [NCBI Gene 25402] {aka CPP32-beta, Lice, Yama}, Bcl2 (BCL2, apoptosis regulator) [NCBI Gene 24224] {aka Bcl-2}, Il6st (interleukin 6 cytokine family signal transducer) [NCBI Gene 25205] {aka Ac1055, Gp130, Il-6rb}, JAK2 (Janus kinase 2) [NCBI Gene 3717] {aka JTK10}, Nppb (natriuretic peptide type B) [NCBI Gene 18158] {aka BNF, BNP, Iso-ANP}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 20848] {aka 1110034C02Rik, Aprf}, RORA (RAR related orphan receptor A) [NCBI Gene 6095] {aka IDDECA, NR1F1, ROR1, ROR2, ROR3, RORa1}, Mff (mitochondrial fission factor) [NCBI Gene 301563] {aka RGD1310230}, CSF1 (colony stimulating factor 1) [NCBI Gene 1435] {aka CSF-1, MCSF, PG-M-CSF}, HTR2A (5-hydroxytryptamine receptor 2A) [NCBI Gene 3356] {aka 5-HT2A, HTR2}, Ppargc1b (PPARG coactivator 1 beta) [NCBI Gene 291567] {aka PGC1beta, Perc}, SOD1 (superoxide dismutase 1) [NCBI Gene 6647] {aka ALS, ALS1, HEL-S-44, IPOA, SOD, STAHP}, ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) [NCBI Gene 25] {aka ABL, BCR-ABL, CHDSKM, JTK7, bcr/abl, c-ABL}, AGT (angiotensinogen) [NCBI Gene 183] {aka ANHU, SERPINA8, hFLT1}, Foxo1 (forkhead box O1) [NCBI Gene 56458] {aka Afxh, FKHR, Fkhr1, Foxo1a}, Mfn2 (mitofusin 2) [NCBI Gene 64476] {aka HSG}, Jak2 (Janus kinase 2) [NCBI Gene 24514], Dnm1l (dynamin 1-like) [NCBI Gene 74006] {aka 6330417M19Rik, Dlp1, Dnmlp1, Drp1, python}, DYRK1B (dual specificity tyrosine phosphorylation regulated kinase 1B) [NCBI Gene 9149] {aka AOMS3, MIRK}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, Calr (calreticulin) [NCBI Gene 64202] - **Diseases:** hypoxia (MESH:D000860), ischemia (MESH:D007511), cardiotoxicity (MESH:D066126), cardiomyopathy (MESH:D009202), myocarditis (MESH:D009205), hypoxic (MESH:D002534), ischemic (MESH:D002545), Mitochondrial impairment (MESH:D028361), inflammation (MESH:D007249), heart injury (MESH:D006335), injury to (MESH:D014947), fibrosis (MESH:D005355), calcium overload (MESH:D019190), cardiomyocyte apoptosis (MESH:D065703), pulmonary hypertension (MESH:D006976), sepsis (MESH:D018805), septic (MESH:D001170), cardiac hypertrophy (MESH:D006332), chronic Chagas cardiomyopathy (MESH:D002598), pathology (MESH:D005598), cardiac dysfunction (MESH:D006331), OMM (MESH:D015433), heart failure (MESH:D006333), CVDs (MESH:D002318), DCM (MESH:D002311), acute myocardial infarction (MESH:D009203), /R (MESH:C580424), myocardial ischemia (MESH:D017202), cardiomyocyte hypertrophy (MESH:D006984), cardiomyocyte death (MESH:D003643), diabetic cardiomyopathy (MESH:D058065), atherosclerosis (MESH:D050197), viral infection (MESH:D014777), Hypothermia (MESH:D007035), I/R injury (MESH:D015427), restenosis (MESH:D023903) - **Chemicals:** Propofol (MESH:D015742), PAE (MESH:C015423), acetyl-CoA (MESH:D000105), tyrosine (MESH:D014443), Intralipid (MESH:C545823), Quercetin (MESH:D011794), RA (MESH:C041376), TAX (MESH:C003377), Zinc (MESH:D015032), punicalagin (MESH:C115642), flavonoid (MESH:D005419), ROS (MESH:D017382), calcium (MESH:D002118), Morphine (MESH:D009020), ellagic acid (MESH:D004610), lipid (MESH:D008055), LPS (MESH:D008070), polyphenol (MESH:D059808), ATP (MESH:D000255), esculetin (MESH:C007628), fatty acid (MESH:D005227), MDA (MESH:D008315), gamma-linolenic acid (MESH:D017965), dexmedetomidine (MESH:D020927), mitoTEMPO (MESH:C555916), STATtic (MESH:C517409), FTY720 (MESH:D000068876), doxorubicin (MESH:D004317), atorvastatin (MESH:D000069059), H2O2 (MESH:D006861), 7,8-DHF (-), superoxide (MESH:D013481), 7,8-Dihydroxyflavone (MESH:C485383), Melatonin (MESH:D008550) - **Species:** Mus musculus (house mouse, species) [taxon 10090], Taxus (genus) [taxon 25628], Punica granatum (granado, species) [taxon 22663], Oryctolagus cuniculus (domestic rabbit, species) [taxon 9986], Godmania aesculifolia (species) [taxon 429669], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116], Paeonia lactiflora (Chinese peony, species) [taxon 35924] - **Mutations:** E180G - **Cell lines:** AC16 — Homo sapiens (Human), Transformed cell line (CVCL_HA69), vascular smooth muscle — Homo sapiens (Human), Finite cell line (CVCL_4009) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12938606/full.md ## Figures 3 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12938606/full.md ## References 118 references — full list in the complete paper: https://tomesphere.com/paper/PMC12938606/full.md --- Source: https://tomesphere.com/paper/PMC12938606