BIRC3-CASP8 axis orchestrates PANoptosis spectrum, shifting destructive cell death to apoptosis in ischemic heart failure.

The progression of heart failure (HF) following myocardial ischemia/reperfusion (I/R) injury is significantly exacerbated by regulated cell death. Unlike the contained nature of apoptosis, lytic cell death forms like pyroptosis and necroptosis trigger potent inflammatory cascades, causing extensive collateral damage to the non-regenerative myocardium. Understanding the integrated regulation of these diverse cell death pathways, termed PANoptosis, is crucial for limiting infarct expansion and preserving cardiac function.

Researchers investigated PANoptosis in both a rat I/R model and an H9c2 cell line OGD/R model (oxygen-glucose deprivation/reperfusion). They characterized cell death using transmission electron microscopy, immunofluorescence, and molecular markers such as C-CASP3, N-GSDMD, and p-MLKL. The functional hierarchy of the BIRC3-CASP8 axis was dissected through AAV-mediated gene transfer to manipulate gene expression and the application of pharmacological inhibitors targeting specific components of the pathway.

I/R injury was confirmed to induce PANoptosis with interdependent crosstalk between its constituent pathways. Mechanistically, BIRC3 emerged as a pivotal checkpoint: its upregulation actively inhibited CASP8, which consequently promoted membrane-rupturing pyroptosis and necroptosis. This lytic cell death mode released inflammatory mediators, propagating damage. > Crucially, BIRC3 silencing disinhibited CASP8, effectively redirecting the cell death machinery toward a more silent, apoptosis-dominant phenotype. This phenotypic shift preserved cell membrane integrity, significantly minimized the release of inflammatory mediators, and effectively halted the propagation of cell death to surrounding healthy cardiomyocytes.