Pathological networks and multi-target interventions in sepsis-associated acute lung injury: from pathogen-host...

Sepsis is a life-threatening organ dysfunction resulting from a dysregulated host response to infection, accounting for an estimated 11 million deaths annually worldwide. Among its most prevalent and severe complications is acute respiratory distress syndrome (ARDS). Traditional research has focused on isolated pathways such as inflammation and oxidative stress; however, the results of clinical trials for related targeted drugs have been less than ideal. The core reason is that sepsis-associated acute lung injury (SA-ALI) is not driven by a single, independent pathway, but rather by an interconnected pathological network activated jointly by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), featuring multiple positive feedback loops. In this network, pathogen virulence factors serve as upstream initiation nodes, while mitochondrial dysfunction acts as a central regulatory hub. Downstream, four major effect modules-immune and inflammatory dysregulation, oxidative stress and coagulation imbalance, bidirectional disruption of the gut-lung axis, and ferroptosis-are linked in series. Multiple links in this network synergistically amplify damage to alveolar epithelium and endothelium, ultimately leading to diffuse pulmonary edema, gas exchange failure, and multi-organ failure.

This paper systematically searched PubMed, Web of Science, and CNKI databases from 2000 to 2026, using the search terms "sepsis, acute lung injury, ferroptosis, gut-lung axis, phage therapy, and mitochondrial-targeted interventions." We screened for literature on fundamental mechanisms, animal studies, clinical cohort studies, and reviews, while excluding low-relevance studies based solely on in vitro cellular validation or lacking in vivo or clinical sample support. Throughout the paper, a three-tier interconnected pathological network serves as the unifying framework. We systematically analyze the interaction patterns between pathogenic microorganisms and the host's immune and metabolic networks, compare the distinct damage pathways induced by virulence factors of different pathogens, and elucidate, layer by layer, the cross-talk among the immune-inflammatory, oxidative stress, gut-lung axis, and ferroptosis modules; At the same time, it categorizes all emerging therapies by stage, conducts critical evaluations based on their clinical translation status, and constructs a phased, sequential, multi-target synergistic treatment framework.

1. The virulence pathways of different bacteria, fungi, and viruses exhibit a pattern of "heterogeneous triggering and downstream convergence," with damage signals from various pathogens ultimately converging at two core network hubs: mitochondrial dysfunction and ferroptosis; 2. There are multilevel positive feedback loops among immune and inflammatory dysregulation, oxidative stress, coagulation disorders, the gut-lung axis, and ferroptosis; blocking a single pathway is offset by compensatory pathways within the network, which explains the clinical failure of single-target drugs; 3. Existing interventions can be classified into five major categories: upstream anti-infection, midstream mitochondrial protection, downstream inhibition of inflammation/ferroptosis, epigenetic regulation, and natural small-molecule adjuvants. Each therapeutic approach has well-defined synergistic targets, and their combined use can simultaneously block multiple damage nodes within the network; 4. The source of infection, age, immune status, and underlying comorbidities reshape the topological structure of the pathological network, leading to heterogeneity in treatment response and necessitating stratified, individualized interventions.

This review overcomes the limitations of traditional reviews-which often present "fragmented discussions focused on a single pathway"-by using an interconnected pathological network as the central thread to link all content throughout. It innovatively proposes a three-tiered network regulation theory; systematically compares the development stages, clinical bottlenecks, and synergistic value of various therapies; and provides a comprehensive theoretical framework for precision stratified treatment of SA-ALI and the identification of new drug targets. Targeting central network nodes such as mitochondria and employing phased, sequential multi-target combination regimens offer superior lung-protective effects compared to single-pathway inhibitors and represent a core research direction for improving the long-term prognosis of patients with sepsis complicated by ARDS.