Macrophage TRPML1 ameliorates post-myocardial infarction inflammation by blocking VDAC1 oligomerization to prevent...

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.