# ROS-Mediated Cardiomyocyte Proliferation and Myocardial Regeneration: Mechanisms and Targeted Strategies for Ischemic Heart Disease **Authors:** Mengqi Chen, Tingting Liu, Fangling Sun, Xin Tian, Wenrong Zheng, Zixin Zhu, Wen Wang PMC · DOI: 10.3390/jcdd13030105 · Journal of Cardiovascular Development and Disease · 2026-02-25 ## TL;DR This review explores how reactive oxygen species (ROS) influence heart cell regeneration and how targeting ROS could help treat heart disease. ## Contribution The paper provides a mechanistic and translational framework for redox-based therapies to promote heart cell proliferation. ## Key findings - ROS can both support and hinder heart cell regeneration depending on their concentration. - Pathological ROS accumulation causes cell cycle arrest and impairs heart function. - Emerging therapies aim to modulate ROS to enhance myocardial regeneration. ## Abstract Cardiovascular disease (CVD) persists as the leading cause of global mortality, with adult mammalian hearts exhibiting limited regenerative capacity. Although cardiomyocytes (CMs) can re-enter the cell cycle and undergo DNA synthesis in response to injury, they fail to complete mitosis and cytokinesis, resulting in a functional blockade of productive proliferation following ischemic or aging-related injury. Reactive oxygen species (ROS) exhibit a context-dependent duality in cardiac regeneration: while maintaining redox homeostasis and supporting developmental signaling at physiological concentrations, pathological ROS accumulation exacerbates myocardial decline by inducing DNA damage response (DDR)-mediated cell cycle arrest at G2/M phase, along with structural and functional impairments. This review examines the mechanisms of ROS generation—from its cellular origins to its molecular drivers—in ischemic heart disease, and explores the modulation of regenerative signaling by oxidative stress. We further critically assess emerging therapeutic interventions targeting ROS-mediated myocardial regeneration. By delineating the functional roles of ROS in cardiac injury and repair, this review provides a mechanistic and translational framework for developing redox-based therapies aimed at promoting cardiomyocyte proliferation and myocardial regeneration after ischemic injury. ## Linked entities - **Diseases:** ischemic heart disease (MONDO:0024644), cardiovascular disease (MONDO:0004995), heart disease (MONDO:0005267) ## Full-text entities - **Genes:** Pcna (proliferating cell nuclear antigen) [NCBI Gene 18538], Tfam (transcription factor A, mitochondrial) [NCBI Gene 21780] {aka Hmgts, mtTFA, tsHMG}, OGG1 (8-oxoguanine DNA glycosylase) [NCBI Gene 4968] {aka HMMH, HOGG1, MUTM, OGH1}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, Cybb (cytochrome b-245 beta chain) [NCBI Gene 66021] {aka Gp91-phox, Nox2}, CACNA1C (calcium voltage-gated channel subunit alpha1 C) [NCBI Gene 775] {aka CACH2, CACN2, CACNA1C-IT2, CACNL1A1, CCHL1A1, CaV1.2}, Ccnb1 (cyclin B1) [NCBI Gene 268697] {aka Ccnb1-rs1, Ccnb1-rs13, CycB1, Cycb-4, Cycb-5, Cycb1-rs1}, SOD1 (superoxide dismutase 1) [NCBI Gene 6647] {aka ALS, ALS1, HEL-S-44, IPOA, SOD, STAHP}, VDAC1 (voltage dependent anion channel 1) [NCBI Gene 7416] {aka PORIN, VDAC-1}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, MCU (mitochondrial calcium uniporter) [NCBI Gene 90550] {aka C10orf42, CCDC109A, HsMCU}, MAPK8 (mitogen-activated protein kinase 8) [NCBI Gene 5599] {aka JNK, JNK-46, JNK1, JNK1A2, JNK21B1/2, PRKM8}, Cdk1 (cyclin dependent kinase 1) [NCBI Gene 12534] {aka Cdc2, Cdc2a, p34}, Akt1 (AKT serine/threonine kinase 1) [NCBI Gene 24185] {aka Akt}, Cdk2 (cyclin dependent kinase 2) [NCBI Gene 12566] {aka A630093N05Rik}, NANOG (Nanog homeobox) [NCBI Gene 79923], VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, CCND1 (cyclin D1) [NCBI Gene 595] {aka BCL1, D11S287E, PRAD1, U21B31}, H3c7 (H3 clustered histone 7) [NCBI Gene 260423] {aka H3.2-221, H3c13, H3c14, H3c15, H3c2, H3c3}, Cdkn1a (cyclin dependent kinase inhibitor 1A) [NCBI Gene 12575] {aka CAP20, CDKI, CIP1, Cdkn1, P21, SDI1}, WEE1 (WEE1 G2 checkpoint kinase) [NCBI Gene 7465] {aka WEE1A, WEE1hu}, NKX2-5 (NK2 homeobox 5) [NCBI Gene 1482] {aka CHNG5, CSX, CSX1, HLHS2, NKX2.5, NKX2E}, HDAC4 (histone deacetylase 4) [NCBI Gene 9759] {aka AHO3, BDMR, HA6116, HD4, HDAC-4, HDAC-A}, NOS2 (nitric oxide synthase 2) [NCBI Gene 4843] {aka HEP-NOS, INOS, NOS, NOS2A}, MEF2C (myocyte enhancer factor 2C) [NCBI Gene 4208] {aka C5DELq14.3, DEL5q14.3, NEDHSIL}, Trp53-ps (transformation related protein 53, pseudogene) [NCBI Gene 22060], Sod2 (superoxide dismutase 2, mitochondrial) [NCBI Gene 20656] {aka MnSOD, Sod-2}, CAT (catalase) [NCBI Gene 847], PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, CGAS (cyclic GMP-AMP synthase) [NCBI Gene 115004] {aka C6orf150, D4, MB21D1, h-cGAS}, MIR1825 (microRNA 1825) [NCBI Gene 100302183] {aka MIRN1825, hsa-mir-1825}, CYBA (cytochrome b-245 alpha chain) [NCBI Gene 1535] {aka CGD4, p22-PHOX}, PITX2 (paired like homeodomain 2) [NCBI Gene 5308] {aka ARP1, ASGD4, Brx1, IDG2, IGDS, IGDS2}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, Aass (aminoadipate-semialdehyde synthase) [NCBI Gene 30956] {aka LKR, LKR/SDH, LOR, LOR/SDH, Lorsdh, SDH}, Tfrc (transferrin receptor) [NCBI Gene 64678] {aka Trfr}, CDKN2A (cyclin dependent kinase inhibitor 2A) [NCBI Gene 1029] {aka ARF, CAI2, CDK4I, CDKN2, CMM2, INK4}, TBX5 (T-box transcription factor 5) [NCBI Gene 6910] {aka HOS}, ACTC1 (actin alpha cardiac muscle 1) [NCBI Gene 70] {aka ACTC, ASD5, CMD1R, CMH11, LVNC4}, Prrx1 (paired related homeobox 1) [NCBI Gene 18933] {aka A230024N07Rik, K-2, MHox1, Pmx, Pmx1, Prx1}, STING1 (stimulator of interferon response cGAMP interactor 1) [NCBI Gene 340061] {aka ERIS, MITA, MPYS, NET23, SAVI, STING}, Ptk2 (PTK2 protein tyrosine kinase 2) [NCBI Gene 14083] {aka FADK 1, FAK, FRNK, Fadk, p125FAK}, POLG (DNA polymerase gamma, catalytic subunit) [NCBI Gene 5428] {aka MIRAS, MTDPS4A, MTDPS4B, PEO, POLG1, POLGA}, CASP3 (caspase 3) [NCBI Gene 836] {aka CPP32, CPP32B, SCA-1}, TNNI3 (troponin I3, cardiac type) [NCBI Gene 7137] {aka CMD1FF, CMD2A, CMH7, RCM1, TNNC1, cTnI}, MEIS1 (Meis homeobox 1) [NCBI Gene 4211], Gsk3b (glycogen synthase kinase 3 beta) [NCBI Gene 56637] {aka 7330414F15Rik, 8430431H08Rik, GSK-3, GSK-3beta, GSK3}, H3P16 (H3 histone pseudogene 16) [NCBI Gene 644914] {aka H3.6, H3F3AP6, p21}, POU5F1 (POU class 5 homeobox 1) [NCBI Gene 5460] {aka OCT3, OCT4, OCT4Borf1, OTF-3, OTF3, OTF4}, MIRLET7B (microRNA let-7b) [NCBI Gene 406884] {aka LET7B, MIRNLET7B, hsa-let-7b, let-7b}, TNNT2 (troponin T2, cardiac type) [NCBI Gene 7139] {aka CMD1D, CMH2, CMPD2, LVNC6, RCM3, TnTC}, Jun (Jun proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 16476] {aka AP-1, Junc, c-jun}, Igf1 (insulin-like growth factor 1) [NCBI Gene 16000] {aka C730016P09Rik, Igf-1, Igf-I}, LOX (lysyl oxidase) [NCBI Gene 4015] {aka AAT10}, Nfe2l2 (nuclear factor, erythroid derived 2, like 2) [NCBI Gene 18024] {aka Nrf2}, VCP (valosin containing protein) [NCBI Gene 7415] {aka CDC48, FTDALS6, TERA, p97}, HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1) [NCBI Gene 3181] {aka HNRNPA2, HNRNPB1, HNRPA2, HNRPA2B1, HNRPB1, IBMPFD2}, Atm (ataxia telangiectasia mutated) [NCBI Gene 11920] {aka C030026E19Rik}, GATA4 (GATA binding protein 4) [NCBI Gene 2626] {aka ASD2, TACHD, TOF, VSD1}, FSD1 (fibronectin type III and SPRY domain containing 1) [NCBI Gene 79187] {aka GLFND, MIR1} - **Diseases:** fibrosis (MESH:D005355), systolic failure (MESH:D054143), hypoxia (MESH:D000860), ischemic (MESH:D002545), MI (MESH:D009203), Complexes I-V (MESH:C537475), inflammation (MESH:D007249), respiratory impairment (MESH:D012131), Ischemic Heart Disease (MESH:D017202), necrotic (MESH:D009336), hypoxic (MESH:D002534), HF (MESH:D006333), death (MESH:D003643), infarct (MESH:D007238), cardiac injury (MESH:D006331), injury to (MESH:D014947), myocardial decline (MESH:D060825), metabolic dysregulation (MESH:D021081), reperfusion injury (MESH:D015427), ETC dysfunction (MESH:D028361), ischemia (MESH:D007511), cardiomyopathy (MESH:D009202), cytotoxic (MESH:D064420), CVD (MESH:D002318), myocarditis (MESH:D009205) - **Chemicals:** HO (MESH:D006695), NaHS (MESH:C025451), H2O2 (MESH:D006861), Cardiolipin (MESH:D002308), Mn3O4 (MESH:C027424), 8-oxoguanine (MESH:C024829), ROS (MESH:D017382), carpaine (MESH:C018479), hydroxyl radical (MESH:D017665), T3 (MESH:D014284), rutin (MESH:D012431), polydopamine (MESH:C568283), N-acetylcysteine (MESH:D000111), quercetin (MESH:D011794), Selenium (MESH:D012643), cyclosporine A (MESH:D016572), MitoQ (MESH:C429014), graphene oxide (MESH:C000628730), ATP (MESH:D000255), polylysine (MESH:D011107), Vitamin C (MESH:D001205), malonate (MESH:C030290), fisetin (MESH:C017875), alginate (MESH:D000464), flavonoid (MESH:D005419), ginsenoside Rb1 (MESH:C442759), superoxide (MESH:D013481), sulfhydryl (MESH:D013438), lactate (MESH:D019344), oxygen (MESH:D010100), 4-HNE (-), calcium (MESH:D002118), D-galactose (MESH:D005690), lipid (MESH:D008055), peroxynitrite (MESH:D030421), hyaluronic acid (MESH:D006820), TCA (MESH:D014238), morroniside (MESH:C488401), edaravone (MESH:D000077553), Fe-S (MESH:D007501), MDA (MESH:D015104) - **Species:** Rattus norvegicus (brown rat, species) [taxon 10116], Danio rerio (leopard danio, species) [taxon 7955], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606] - **Cell lines:** H9C2 — Rattus norvegicus (Rat), Spontaneously immortalized cell line (CVCL_0286) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC13026799/full.md ## Figures 2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC13026799/full.md ## References 99 references — full list in the complete paper: https://tomesphere.com/paper/PMC13026799/full.md --- Source: https://tomesphere.com/paper/PMC13026799