The networked landscape of cell death in sepsis: from dynamic pathway to node-targeted therapies

Although research into programmed cell death in sepsis has spanned several decades, mortality rates remain high, and no therapy specifically targeting cell death pathways has yet achieved clinical translation.

In this review, we propose a temporal and spatial framework in which sepsis-related cell death unfolds along three integrated axes.

First, the sequential transformation from early pyroptosis and NETosis (driving hyperinflammation) to mid-stage necroptosis (amplifying tissue damage) to late lymphocyte apoptosis (mediating immunosuppression), with distinct cellular responses in immune cells versus parenchymal tissues. Second, we have distilled complex pathway interactions into three converging decision nodes, RIPK1 ubiquitination status, caspase-8 activity, and membrane pore executors (GSDMD/MLKL/NINJ1), whose coordinated state determines whether cells undergo inflammatory lytic death or silent apoptosis. Third, we describe why single-pathway inhibitors fail in preclinical sepsis studies, and propose a stage-specific therapeutic strategy: inhibit GSDMD early to block pyroptosis; modulate RIPK1 mid-phase to limit RIPK1-dependent inflammatory or necroptotic pathology; and restore lymphoid homeostasis late via caspase-3 inhibition or IL-7 therapy. Finally, we conclude by outlining a translational roadmap prioritising biomarker development, patient stratification, and adaptive trial designs for future research.