Regulatory Network of Pyroptosis, Ferroptosis, and Cuproptosis in Sepsis-Associated Multiple Organ Dysfunction: The Initiation–Amplification–Effector Cascade Hypothesis and Translational Insights
Year: 2026
Type: article
Abstract: Sepsis-associated multiple organ dysfunction syndrome (MODS) is a life-threatening clinical complication with persistently high global mortality, and specific therapeutic strategies remain limited. Pyroptosis and ferroptosis are well-documented regulated cell-death modalities in septic tissue injury, whereas the pathogenic role of cuproptosis in sepsis is supported only by limited pre-clinical data. Existing reviews mainly describe pairwise crosstalk between two of these cell-death pathways, but an integrated conceptual framework uniting all three modalities remains poorly defined. In this narrative review, we synthesize current evidence on the core molecular machinery governing pyroptosis, ferroptosis, and cuproptosis in sepsis-induced MODS and dissect their reciprocal regulatory crosstalk. We further propose a hypothetical initiation–amplification–effector cascade model in which mitochondrial dysfunction, oxidative stress, and iron–copper dyshomeostasis are candidate shared signaling hubs that may contribute to multi-organ pathological damage. We highlight major translational bottlenecks, including insufficient human clinical evidence, experimental heterogeneity among pre-clinical models, and an incomplete understanding of cuproptosis during sepsis. Moreover, we discuss candidate biomarkers and multi-target therapeutic strategies targeting this interconnected cell-death network. The evidence is mostly pairwise; no study has measured all three execution programs in one septic model. The triple-pathway framework is therefore an inference, not an observed network.
Source: Biology
Institution: First Hospital of China Medical University
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,258
OpenAlex ID: W7225742088