Macrophage PARP7 Alleviates Septic Cardiomyopathy by Interacting With TBK1 and Suppressing TBK1-Driven Inflammatory Response.

Septic cardiomyopathy is a life-threatening complication of sepsis, and an uncontrolled inflammatory response represents a key pathogenic mechanism. PARP7 negatively regulates the IFN-I signaling pathway through a mono-ADP-ribosylation-dependent interaction with TBK1. Here, through comprehensive analysis of the expression profile of the PARP family in LPS-treated myocardial tissues, we propose that PARP7 may be associated with septic cardiomyopathy. Then, we demonstrate that PARP7 deficiency exacerbates LPS-induced septic cardiomyopathy in vivo. Integrated single-nucleus and single-cell RNA sequencing analyses demonstrate that PARP7 is predominantly upregulated in macrophages in the hearts of LPS-treated mice. Using an AAV9-based delivery system, we further validated the cardioprotective role of macrophage-specific PARP7 in murine models of sepsis induced by either LPS or CLP. Mechanistically, PARP7 interacts with TBK1 to mediate its ADP-ribosylation, thereby suppressing the TBK1-driven inflammatory response in macrophages. The snRNA-seq and cytokine array data collectively support a critical role for PARP7 as a molecular "brake" that constrains excessive macrophage inflammation. In conclusion, this work identifies a macrophage-specific PARP7-TBK1 regulatory axis in septic cardiomyopathy and highlights the therapeutic potential of macrophage-specific PARP7 overexpression.