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

ABSTRACT 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.