Academic Journal
SIRT3 in post-myocardial infarction macrophage reprogramming: linking mitochondrial fitness to inflammation resolution and repair.
| Τίτλος: | SIRT3 in post-myocardial infarction macrophage reprogramming: linking mitochondrial fitness to inflammation resolution and repair. |
|---|---|
| Συγγραφείς: | Li X; Qihuang College, Guizhou University of Traditional Chinese Medicine, Guiyang, China., Luo X; School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China., Zhang Z; School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China., Tang L; School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China., Meng X; Qihuang College, Guizhou University of Traditional Chinese Medicine, Guiyang, China. |
| Πηγή: | Frontiers in immunology [Front Immunol] 2026 Jul 08; Vol. 17, pp. 1848626. Date of Electronic Publication: 2026 Jul 08 (Print Publication: 2026). |
| Τύπος έκδοσης: | Journal Article; Systematic Review |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Lausanne : Frontiers Research Foundation] |
| Ιατρικοί όροι (MeSH): | Macrophages*/metabolism , Macrophages*/immunology , Myocardial Infarction*/metabolism , Myocardial Infarction*/pathology , Myocardial Infarction*/immunology , Sirtuin 3*/metabolism , Mitochondria*/metabolism , Cellular Reprogramming*, Inflammation/metabolism ; Inflammation/immunology ; Reactive Oxygen Species/metabolism ; Humans ; Animals ; Efferocytosis ; Metabolic Reprogramming |
| Περίληψη: | Myocardial infarction (MI) remains a leading cause of cardiovascular mortality worldwide. Despite significant advances in reperfusion strategies and pharmacotherapy, persistent inflammation and adverse ventricular remodeling continue to underlie poor long-term clinical outcomes. Macrophages serve as central orchestrators of post-MI healing, coordinating the clearance of necrotic debris, resolution of inflammation, remodeling of the extracellular matrix, and maturation of the fibrotic scar. However, the conventional M1/M2 dichotomy fails to fully capture the dynamic, phenotypically heterogeneous, and metabolically constrained macrophage states that emerge during infarct healing. In this review, we synthesize current evidence supporting a trajectory-based framework for macrophage reprogramming following MI and emphasize mitochondrial fitness as a critical determinant governing the transition from sustained inflammation to reparative resolution. We summarize key metabolic checkpoints regulating this functional shift-including glycolytic rewiring, tricarboxylic acid (TCA) cycle remodeling, mitochondrial reactive oxygen species (mtROS) accumulation, efferocytosis, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and mitochondrial quality control. Furthermore, we advance the hypothesis that SIRT3-the principal mitochondrial NAD+-dependent deacetylase-may act as a central regulatory node linking mitochondrial protein acetylation to macrophage state transitions after MI. Specifically, we outline a staged dual-axis working model, generated from convergent but largely indirect evidence, in which the SOD2-mtROS axis is more closely linked to early nonresolving inflammation, whereas the PDHA1-metabolic flexibility axis may be more relevant to efferocytosis-associated reparative transition. We further highlight NAD+ availability as an upstream limiting factor that may constrain SIRT3 activity in macrophages under ischemic-inflammatory stress. Finally, we critically evaluate the current evidence hierarchy, human translatability, therapeutic strategies, and key translational challenges-emphasizing considerations of timing, cellular specificity, delivery modalities, and target engagement. Although macrophage-specific causal evidence in myocardial infarction (MI) remains sparse, this framework is intended as a mechanistically coherent and experimentally tractable working hypothesis to guide future investigations into macrophage immunometabolism and mitochondrial-targeted interventions in post-infarction cardiac repair. Accordingly, the proposed framework should be viewed as a testable working hypothesis rather than a settled causal model of macrophage fate control in MI. (Copyright © 2026 Li, Luo, Zhang, Tang and Meng.) |
| Competing Interests: | The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. |
| References: | mBio. 2021 Feb 2;12(1):. (PMID: 33531400) Circ Res. 2020 Aug 14;127(5):664-676. (PMID: 32434457) Cardiovasc Res. 2025 Apr 22;121(2):267-282. (PMID: 39658136) J Control Release. 2026 Mar 10;391:114647. (PMID: 41565184) Mol Cell Biochem. 2025 Dec;480(12):6077-6109. (PMID: 40750734) Basic Res Cardiol. 2024 Apr;119(2):261-275. (PMID: 38436707) Int J Med Sci. 2024 Aug 12;21(11):2139-2148. (PMID: 39239543) Nat Rev Cardiol. 2025 Jun;22(6):431-442. (PMID: 39743564) J Biomed Mater Res A. 2025 May;113(5):e37924. (PMID: 40341794) Front Cardiovasc Med. 2023 May 05;10:1136252. (PMID: 37215542) Adv Sci (Weinh). 2024 Jun;11(24):e2306388. (PMID: 38477522) Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2022 Aug 28;47(8):1108-1119. (PMID: 36097779) Biochem Pharmacol. 2021 Oct;192:114665. (PMID: 34181898) Cell Death Dis. 2025 May 15;16(1):381. (PMID: 40368890) PLoS Pathog. 2023 May 8;19(5):e1011381. (PMID: 37155697) Cell Rep. 2022 Apr 12;39(2):110660. (PMID: 35417703) Cell Rep. 2021 Nov 2;37(5):109917. (PMID: 34731617) Biomaterials. 2025 Mar;314:122890. (PMID: 39427429) Int J Biol Sci. 2025 May 15;21(8):3444-3460. (PMID: 40520025) Acta Pharmacol Sin. 2024 Jun;45(6):1175-1188. (PMID: 38459256) Biomed Pharmacother. 2024 Jan;170:116004. (PMID: 38086147) Redox Biol. 2022 Aug;54:102384. (PMID: 35777198) Protein Cell. 2021 Mar;12(3):194-212. (PMID: 32845445) J Exp Clin Cancer Res. 2025 Jul 4;44(1):193. (PMID: 40616124) Pharmacol Res. 2024 Nov;209:107468. (PMID: 39426469) Adv Sci (Weinh). 2024 Jun;11(21):e2308910. (PMID: 38582507) Cardiovasc Res. 2026 Mar 26;122(3):397-411. (PMID: 41554295) Circ Res. 2024 Sep 27;135(8):841-855. (PMID: 39234697) Theranostics. 2025 Aug 30;15(18):9580-9600. (PMID: 41041054) Bioact Mater. 2026 Feb 04;60:590-606. (PMID: 41727273) Eur J Pharmacol. 2025 Dec 5;1008:178376. (PMID: 41241334) Front Pharmacol. 2025 Jan 10;15:1503757. (PMID: 39867660) Arterioscler Thromb Vasc Biol. 2021 Feb;41(2):714-730. (PMID: 33327751) Biomed Pharmacother. 2024 Mar;172:116224. (PMID: 38308970) Adv Sci (Weinh). 2025 Nov;12(42):e06337. (PMID: 40827661) Adv Sci (Weinh). 2026 Jan;13(5):e10991. (PMID: 41214880) J Mol Cell Cardiol. 2024 Nov;196:152-167. (PMID: 39089570) Front Immunol. 2022 Nov 02;13:950441. (PMID: 36405744) Int Immunopharmacol. 2024 Apr 20;131:111883. (PMID: 38503016) Eur J Immunol. 2021 Jan;51(1):250-252. (PMID: 32761616) JCI Insight. 2024 Mar 8;9(5):. (PMID: 38456501) Acta Biomater. 2026 Feb;211:18-32. (PMID: 39182804) J Cell Mol Med. 2025 Oct;29(20):e70846. (PMID: 41139809) Int J Mol Sci. 2020 Jul 24;21(15):. (PMID: 32722183) Metabolism. 2022 Oct;135:155275. (PMID: 35932995) Phytomedicine. 2023 Jan;108:154494. (PMID: 36279758) Sci Rep. 2026 Mar 19;16(1):. (PMID: 41857111) Nat Cardiovasc Res. 2025 Nov;4(11):1550-1572. (PMID: 41184578) J Nanobiotechnology. 2025 Jun 13;23(1):439. (PMID: 40514650) Circulation. 2026 Mar 17;153(11):826-844. (PMID: 41492949) Curr Med Chem. 2026 Jan 13;:. (PMID: 41572764) Mol Biol Rep. 2021 Apr;48(4):3089-3096. (PMID: 33866495) Phytother Res. 2025 Nov;39(11):5198-5221. (PMID: 41022487) Ageing Res Rev. 2025 Feb;104:102654. (PMID: 39755174) Circulation. 2022 May 17;145(20):1542-1556. (PMID: 35430895) Small Methods. 2025 Nov;9(11):e00818. (PMID: 40923210) Nat Commun. 2023 Nov 20;14(1):7555. (PMID: 37985764) Circulation. 2024 Jun 18;149(25):1982-2001. (PMID: 38390737) Transl Psychiatry. 2025 Mar 30;15(1):112. (PMID: 40159484) Rejuvenation Res. 2020 Dec;23(6):453-464. (PMID: 32228121) Thromb Haemost. 2020 Jan;120(1):168-180. (PMID: 31858519) J Clin Invest. 2023 Feb 15;133(4):. (PMID: 36480284) Cardiovasc Res. 2025 Dec 31;121(17):2759-2776. (PMID: 41223038) Mater Today Bio. 2026 Feb 05;37:102891. (PMID: 41716340) Basic Res Cardiol. 2025 Oct;120(5):889-912. (PMID: 40817969) Biomaterials. 2022 Aug;287:121656. (PMID: 35792386) Circulation. 2025 Apr;151(13):e771-e862. (PMID: 40014670) Cell Stem Cell. 2025 Dec 4;32(12):1849-1868.e15. (PMID: 41205597) Phytomedicine. 2025 Jan;136:156260. (PMID: 39579610) Mater Today Bio. 2025 Nov 24;35:102600. (PMID: 41399354) ACS Nano. 2026 Feb 24;20(7):5687-5707. (PMID: 41665146) Theranostics. 2021 Feb 15;11(8):3981-3995. (PMID: 33664876) Obesity (Silver Spring). 2023 Apr;31(4):1050-1063. (PMID: 36894333) Cardiovasc Res. 2023 May 2;119(3):772-785. (PMID: 35950218) J Clin Invest. 2024 Aug 27;134(19):. (PMID: 39190625) Cells. 2024 Mar 05;13(5):. (PMID: 38474420) Nat Commun. 2022 Aug 6;13(1):4580. (PMID: 35933399) Adv Sci (Weinh). 2023 Nov;10(32):e2304627. (PMID: 37767946) Elife. 2024 May 22;12:. (PMID: 38775664) Nat Cardiovasc Res. 2024 Nov;3(11):1337-1355. (PMID: 39433910) J Adv Res. 2026 Jun;84:717-735. (PMID: 40939891) Cell Death Differ. 2023 Feb;30(2):304-312. (PMID: 36447047) J Am Heart Assoc. 2022 Dec 20;11(24):e027228. (PMID: 36515244) Br J Pharmacol. 2020 Oct;177(20):4645-4665. (PMID: 32726464) Exp Mol Med. 2025 Nov;57(11):2643-2656. (PMID: 41258072) iScience. 2025 Oct 16;28(11):113790. (PMID: 41323268) Mater Today Bio. 2025 Aug 22;34:102234. (PMID: 40893347) Mater Today Bio. 2025 Dec 03;36:102631. (PMID: 41560785) Am J Physiol Cell Physiol. 2024 Sep 1;327(3):C571-C586. (PMID: 38981605) Circ Res. 2022 Nov 11;131(11):893-908. (PMID: 36268709) Int Immunopharmacol. 2026 Jan 15;169:116019. (PMID: 41389666) Mol Neurodegener. 2026 Jan 03;21(1):8. (PMID: 41484627) Sci Rep. 2025 May 17;15(1):17165. (PMID: 40382427) Biomed Pharmacother. 2024 Jun;175:116689. (PMID: 38703508) Circ Res. 2022 May 27;130(11):1682-1697. (PMID: 35440174) |
| Contributed Indexing: | Keywords: NAD+; SIRT3; efferocytosis; immunometabolism; inflammation resolution; macrophage reprogramming; mitochondrial fitness; myocardial infarction |
| Substance Nomenclature: | EC 3.5.1.- (Sirtuin 3) 0 (Reactive Oxygen Species) |
| Entry Date(s): | Date Created: 20260723 Date Completed: 20260723 Latest Revision: 20260813 |
| Update Code: | 20260814 |
| PubMed Central ID: | PMC13388082 |
| DOI: | 10.3389/fimmu.2026.1848626 |
| PMID: | 42488660 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1664-3224 |
|---|---|
| DOI: | 10.3389/fimmu.2026.1848626 |