Potential of biomarker-based enrichment strategies to identify critically ill patients for emerging cell death interventions

Critically ill patients admitted to the intensive care unit (ICU) frequently suffer from sepsis and severe multiple organ dysfunction with underlying widespread cell death. Pyroptosis and ferroptosis are regulated cell death forms that may serve as potential therapeutic targets. Pyroptosis is a major detrimental factor driving sepsis, which typically results in excessive oxidative stress potentially inducing ferroptotic organ injury. Here, we show that ICU patients with simultaneous pyro- and ferroptosis-positive signatures have the lowest survival probability. This is reflected by significantly elevated levels of pyroptosis-related biomarkers interleukin-1 receptor antagonist (IL-1Ra), IL-18, and growth and differentiation factor-15 (GDF15), as well as the ferroptosis-related biomarkers malondialdehyde (MDA) and catalytic iron (Fe_c). Moreover, combining these biomarkers with IL-1α, IL-6, IL-10, TNF, and chitinase-3-like protein 1 further improves clinical outcome prediction. The daily monitoring of pyro- and ferroptosis signatures reveals potential intervention opportunities, such as anakinra, tadekinig alfa, lead ferroptosis inhibitors, or a combination thereof. In summary, our findings demonstrate that a targeted biomarker panel enables predictive enrichment of ICU patients, paving the way for timely intervention strategies against pyroptosis or ferroptosis.