Introduction: Sepsis as a Signaling and Metabolic Challenge
Sepsis is a complex, life-threatening syndrome driven by dysregulated immune responses, systemic inflammation, and widespread metabolic disruption. Traditional treatments, centered on antibiotics and early goal-directed therapy, often fall short due to the dynamic and heterogeneous nature of the disease. A growing body of research points to a network of signaling pathways and mitochondrial metabolism that together shape disease progression and organ dysfunction.
Key Signaling Pathways in Sepsis
Sepsis engages a constellation of signaling cascades that control immune activation and inflammation. Central among them are the NF-κB, JAK/STAT, Toll-like receptor (TLR), and MAPK pathways, each contributing to cytokine production, immune cell activation, and cell fate decisions.
NF-κB: The Inflammatory Switch
The canonical NF-κB pathway is triggered by lipopolysaccharide (LPS) and other PAMPs, initiating a cascade via TLRs that culminates in NF-κB translocation to the nucleus. This promotes transcription of pro-inflammatory mediators such as TNF-α and IL-1β and influences apoptosis and immune cell recruitment. The non-canonical NF-κB pathway adds another layer of regulation, operating through distinct kinases and subunit combinations. Both branches can amplify systemic inflammation and tissue injury in sepsis.
JAK/STAT: Growth, Survival, and Inflammation
Cytokines like IFN-γ and IL-6 engage their receptors to activate JAKs, which phosphorylate STAT proteins. Phosphorylated STATs form dimers, migrate to the nucleus, and regulate genes tied to inflammation, cell survival, and differentiation. Aberrant JAK/STAT signaling can worsen organ dysfunction by impairing immune regulation and promoting prolonged inflammatory states.
<h2=NLRP3 Inflammasome and Pyroinflammation
A two-step model governs NLRP3 inflammasome activation in sepsis. Priming by PAMPs/DAMPs upregulates NLRP3 expression, while activation signals such as potassium efflux drive complex assembly with ASC and pro-caspase-1. Caspase-1 then processes IL-1β and IL-18, fueling pyroinflammation. This pathway links innate sensing to cytokine maturation and organ injury in septic states.
Hypoxia, HIF-1α, and Inflammatory Regulation
Sepsis can create regions of normoxia and hypoxia, altering HIF-1α stability and activity. Under low oxygen, HIF-1α augments inflammatory gene expression and interacts with NF-κB signaling. This crosstalk contributes to the dysregulated immune response and may influence vascular and metabolic adaptations during sepsis.
Metabolic Reprogramming and Mitochondrial Dysfunction
Energy generation shifts in septic cells, with fatty acid oxidation and oxidative phosphorylation often suppressed. Mitochondrial transcription factor A (TFAM) helps maintain mitochondrial genome integrity, but its function can be impaired in sepsis. Likewise, brain- and muscle- relevant factors such as NRF1/NRF2, and the master regulator PGC-1α modulate mitochondrial biogenesis and energy production. Diminished PGC-1α activity reduces mitochondrial biogenesis, exacerbating energy failure and cellular damage during sepsis.
A Call for Dynamic, Multi-Target Therapeutics
Given the interconnected signaling networks and metabolic disturbances, static single-target interventions are unlikely to yield durable outcomes. A personalized, multi-target approach that monitors pathway activity in real time could moderate hyperinflammation, preserve immune homeostasis, and restore metabolic balance. Potential strategies include selective pathway modulation, combination therapies, and dynamic dosing guided by biomarkers and pathway activity profiles. Translational challenges remain, but this framework holds promise for reducing organ dysfunction and improving prognosis.
Clinical and Research Implications
Future work should map the crosstalk between NF-κB, JAK/STAT, TLR, MAPK, HIF-1α, and metabolic regulators across sepsis stages. Biomarker-driven patient stratification could enable real-time adjustment of therapies, aligning treatment with individual signaling and metabolic states. Progress in this field could translate mechanistic insights into precise, dynamic clinical interventions that improve survival and recovery for septic patients.
Conclusion: A Path Toward Precision Sepsis Care
Sepsis emerges from a complex tapestry of signaling pathways and mitochondrial dysfunction. By decoding these networks and embracing dynamic, multi-target strategies, clinicians may move beyond one-size-fits-all treatments toward personalized interventions that balance immune responses with metabolic needs, ultimately improving outcomes in this high-stakes condition.
