# Cell death mechanisms in heat stroke and sepsis: ZBP1 and caspase-11 as molecular sensors driving the MLKL/GSDMD death execution axis

## TL;DR

Heat stroke and sepsis cause similar organ damage through distinct but related cell death pathways, suggesting new treatment strategies.

## Contribution

This review highlights ZBP1 and caspase-11 as molecular sensors that drive shared cell death mechanisms in heat stroke and sepsis.

## Key findings

- ZBP1 initiates necroptosis in heat stroke by activating the MLKL pathway.
- Caspase-11 triggers pyroptosis in sepsis via the GSDMD pathway.
- Both pathways converge to cause widespread organ damage, suggesting common therapeutic targets.

## Abstract

Heat stroke and sepsis are a pair of acute critical illnesses with distinct underlying causes yet remarkably similar final outcomes. Heat stroke arises from high-temperature environments, disrupting the body’s heat production and dissipation balance; sepsis stems from infection, triggering an uncontrollable inflammatory storm. Both conditions carry extremely high mortality rates and poor prognoses, causing near-total damage to organs and tissues throughout the body. Existing clinical treatments cannot fully reverse the damage inflicted by these diseases. Recent studies have identified necroptosis mediated by the Z-DNA-binding protein 1 (ZBP1) - receptor interaction protein kinase 3 (RIPK3) - mixed lineage kinase-like protein (MLKL) signaling pathway and pyroptosis mediated by the cysteine-aspartic acid proteases-11 (caspase-11) - Gasdermin D (GSDMD) pathway as key mechanisms in heat stroke and sepsis, respectively. Therefore, this review synthesizes recent research findings to analyze the convergent cellular programmed death mechanisms of these two distinct conditions from the perspectives of molecular sensors (a probe for disease triggers) and cell death effectors: ZBP1 senses heat stress, while caspase-11 responds to LPS signaling, initiating downstream membrane-breaching mechanisms executed by MLKL and GSDMD. These processes converge and jointly drive organ damage. The shared pathological outcomes of these distinct diseases suggest that developing broad-spectrum inhibitors targeting their common downstream cell death pathways may represent a novel therapeutic direction.