Non-apoptotic Regulated Cell Death Mechanisms in Sepsis and their Therapeutic Potential

Regulated cell death (RCD) plays an important role in the pathophysiology of sepsis. Traditionally dominated by the concept of apoptosis, the understanding of cell death has significantly expanded to include a range of highly regulated, non-apoptotic mechanisms such as ferroptosis, necroptosis, pyroptosis, parthanatos, and NETosis. This review describes recent advances in the molecular pathways underpinning these RCDs and explores their contributions to inflammatory tissue damage during sepsis and ischemia/reperfusion injury. We highlight the key molecular drivers and signalling cascades for each form of RCD and how thei could interact during sepsis. Also, we present the effects of commonly used medication during sepsis and septic shock in the intensive care unit on RCD. By integrating current evidence, we propose that therapeutic modulation of RCD offers a promising avenue for reducing organ dysfunction and mortality in critical illness or could pose as biomarkers in evaluating the sepsis-associated organ injury.