Journal Article

DKFZ-2026-00488

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Activation of IRF3 in cardiomyocytes impairs mitochondrial oxidative function through PGC-1α inhibition and drives heart failure.

Kumari, M. ; Evangelakos, I. ; Deshpande, A. ; De Jong, K. A. ; Schmiedel, N. ; Palacio-Escat, N. ; Chaves-Filho, A. d. B.DKFZ* ; Frias-Soler, R. C.DKFZ* ; Klinke, G. ; Roh, H. C. ; Lange, L. ; Berlin, M. ; Fuh, M. M. ; Buss, J. J. ; Tian, T. ; Lerchenmüller, C. ; Freichel, M. ; Schulze, A.DKFZ* ; Nikolaev, V. O. ; Eschenhagen, T. ; Rosen, E. D. ; Scheja, L. ; Rangrez, A. Y. ; Heeren, J. ; Frey, N.

2026
Springer Nature [London]

Abstract: Heightened sterile inflammation and mitochondrial metabolic dysfunction drives the pathophysiology of heart failure in ischemic cardiomyopathy. Yet, the transcriptional regulators within cardiomyocytes driving crosstalk between inflammation and energy metabolism remain ill-defined. Here we identify elevated Ser396/Ser398 phosphorylation of the type I interferon (IFN) response regulating transcription factor IRF3 in the myocardium of patients and male mice with ischemic cardiomyopathy. Cardiomyocyte-specific IRF3 deficiency attenuates ischemia induced contractile dysfunction. Conversely, IRF3 activation in cardiomyocytes through a phosphomimetic IRF3 mutant represses Ppargc1α expression leading to dysfunctional mitochondrial oxidative phosphorylation, altered metabolic flux in the pentose phosphate pathway/TCA cycle, impaired NAD metabolism and an excessive type I IFN activation, collectively detrimental for cardiac function. Restoring cardiomyocyte-specific Ppargc1α expression in IRF3-overexpressor male mice attenuates contractile dysfunction by augmenting a metabolic shift towards fatty acid oxidation and decreasing inflammatory fibrotic responses. These findings identify IRF3 activation in cardiomyocytes as a transcriptional nexus between cardiac inflammation and metabolic fuel switch contributing to heart failure progression.

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Contributing Institute(s):

1. Metabolismus und Microenvironment (A410)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2026

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