Macrophage TRPML1 ameliorates post-myocardial infarction inflammation by blocking VDAC1 oligomerization to prevent ferroptosis and cGAS-STING activation.

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.