Activation of the cGAS–STING pathway mediated by IRGM1 contributes to the development of restrictive cardiomyopathy induced by cTnIR193H mutation

Restrictive cardiomyopathy (RCM) is a rare, fatal disorder that rapidly progresses in children. Troponin I3, cardiac type (TNNI3), which encodes cardiac troponin I (cTnI), represents the most common genetic cause. Although cTnI mutations are known to increase myofilament calcium sensitivity and impair diastolic function, this mechanism alone does not fully account for disease pathogenesis. Recent studies have revealed that the immune system plays an important role in cardiovascular diseases; however, its involvement in RCM remains unclear. Here, we generated a classic cTnIR193H mouse model using CRISPR/Cas9. Cardiac RNA sequencing analysis indicated marked activation of innate immune pathways. Moreover, biotin-mediated proximity labeling combined with quantitative mass spectrometry identified differential interactors of the cTnIR193H mutant, with immunity-related GTPase M1 (IRGM1) emerging as the most significantly altered immune-related protein. Notably, the cTnIR193H mutation enhances binding to IRGM1 without affecting its expression, thereby indirectly inhibiting its normal function. This aberrant interaction activates the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway and elicits a type I interferon response in the hearts of RCM mice. Furthermore, treatment with the STING inhibitor C176 partially restored diastolic function and significantly alleviated cardiac fibrosis. Taken together, this study reveals for the first time that immune mechanisms play a crucial role in RCM pathogenesis and provides a potential therapeutic target for RCM treatment from an immunological perspective.