Academic Journal
Macrophage TRPML1 ameliorates post-myocardial infarction inflammation by blocking VDAC1 oligomerization to prevent ferroptosis and cGAS-STING activation.
| Τίτλος: | Macrophage TRPML1 ameliorates post-myocardial infarction inflammation by blocking VDAC1 oligomerization to prevent ferroptosis and cGAS-STING activation. |
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| Συγγραφείς: | Zhao X; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Wang J; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Wang Z; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Du H; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Li H; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Wu T; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Yang K; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Xie L; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Zhang M; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Wang J; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Li P; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Lv C; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Deng Y; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Ji H; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Zhang Y; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Li X; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China., Yuan Y; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China. Electronic address: yuany@hrbmu.edu.cn., Du Z; Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (National Key Laboratory of Frigid Cardiovascular Disease), Harbin, 150081, China; State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, 999078, Macau. Electronic address: duzm@hrbmu.edu.cn. |
| Πηγή: | Free radical biology & medicine [Free Radic Biol Med] 2026 Aug 16; Vol. 252, pp. 166-183. Date of Electronic Publication: 2026 May 04. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Science Country of Publication: United States NLM ID: 8709159 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4596 (Electronic) Linking ISSN: 08915849 NLM ISO Abbreviation: Free Radic Biol Med Subsets: MEDLINE |
| Imprint Name(s): | Publication: Tarrytown, NY : Elsevier Science Original Publication: New York : Pergamon, c1987- |
| Ιατρικοί όροι (MeSH): | cGAS-STING Signaling Pathway*/immunology , Ferroptosis*/immunology , Macrophages*/metabolism , Macrophages*/pathology , Myocardial Infarction*/genetics , Myocardial Infarction*/immunology , Myocardial Infarction*/metabolism , Myocardial Infarction*/pathology , Transient Receptor Potential Channels*/metabolism , Transient Receptor Potential Channels*/genetics , Voltage-Dependent Anion Channel 1*/metabolism , Voltage-Dependent Anion Channel 1*/genetics, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase/metabolism ; Inflammation/pathology ; Inflammation/metabolism ; Inflammation/genetics ; Myocytes, Cardiac/metabolism ; STING Protein/metabolism ; Animals ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Oxidative Stress |
| Περίληψη: | Precise modulation of the inflammatory response is critical for clearing damaged cardiomyocytes and promoting tissue regeneration after myocardial infarction (MI). Transient receptor potential mucolipin 1 (TRPML1) is an endo/lysosomal cation channel involved in regulating lysosomal biogenesis, Fe2+ homeostasis, and phagocytic function; however, its role in post-MI inflammation remains unclear. This study shows that TRPML1 was significantly downregulated at both the protein and transcriptional levels in mouse cardiac tissue on days 3 and 7 post-MI. Using genetic lineage tracing, we found that macrophage-specific overexpression of TRPML1 attenuated the M1-dominant inflammatory response while enhancing M2-mediated repair in the infarcted area, ultimately reducing infarct size and improving cardiac function. In vitro co-culture experiments further demonstrated that activating macrophage TRPML1 restored the viability and collagen synthesis capacity of cardiac fibroblasts impaired by lipopolysaccharide (LPS). Mechanistically, TRPML1 directly targets Voltage-Dependent Anion Channel 1 (VDAC1) and inhibits its oligomerization, thereby reducing oxidative stress and ferroptosis in macrophages, and blocking mitochondrial DNA (mtDNA) escape into the cytoplasm and the subsequent activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. This inhibition significantly alleviated the downstream pro-inflammatory cytokine storm. Importantly, inhibition of VDAC1 oligomerization with NSC 15364 rescued the ferroptosis and cardiac inflammation phenotypes in macrophage-specific TRPML1 knockout (Mac-TRPML1 KO) mice post-MI. In summary, our study identifies macrophage TRPML1 as a key metabolic checkpoint that regulates post-MI repair by controlling macrophage ferroptosis and cardiac fibroblast activation. We propose that targeting the TRPML1-VDAC1-cGAS-STING signaling axis may serve as a novel therapeutic strategy for post-MI inflammation. (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Ferroptosis; Inflammation; Myocardial infarction; TRPML1; VDAC1 oligomerization; cGAS-STING |
| Substance Nomenclature: | EC 2.7.7.- (cGAS protein, mouse) EC 2.7.7.86 (Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase) 0 (Mcoln1 protein, mouse) 0 (STING Protein) 0 (Sting1 protein, mouse) 0 (Transient Receptor Potential Channels) 0 (Vdac1 protein, mouse) EC 1.6.- (Voltage-Dependent Anion Channel 1) |
| Entry Date(s): | Date Created: 20260507 Date Completed: 20260613 Latest Revision: 20260617 |
| Update Code: | 20260618 |
| DOI: | 10.1016/j.freeradbiomed.2026.05.006 |
| PMID: | 42092410 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1873-4596 |
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| DOI: | 10.1016/j.freeradbiomed.2026.05.006 |