Decoding the signaling networks and metabolic dysregulation underlying sepsis

Background：

Sepsis is a complex clinical syndrome characterized by dysregulated immune responses, systemic inflammation, and multi-organ dysfunction. It involves intricate interactions among multiple signaling pathways, including NF-κB, JAK/STAT, TLR, MAPK, HIF-1α, and Nrf2/Keap1, which collectively regulate immune activation, inflammation, and cellular metabolism. Mitochondrial dysfunction and metabolic reprogramming further contribute to its pathogenesis by impairing energy production and immune cell function. Conventional treatments, primarily reliant on antibiotics and early goal-directed therapy, often yield limited efficacy. Emerging research suggests that selective inhibition of key pathways may mitigate hyperinflammation and prevent organ failure. However, due to the dynamic and heterogeneous nature of sepsis, static single-target interventions are insufficient. Instead, a personalized, multi-target modulatory approach is essential, enabling real-time adjustment of therapeutic strategies based on signaling pathway activity. Such an approach could more precisely regulate inflammatory responses, immune homeostasis, and metabolic disturbances while minimizing side effects. Future research should focus on translating these mechanistic insights into clinical applications, offering new hope for improving sepsis prognosis through dynamic, precise, and individualized treatment strategies.

Research progress：

The research conducted by Professor Zou Zui and his team focuses on the immunoregulatory mechanisms in sepsis. As a life-threatening systemic inflammatory response syndrome triggered by infection, sepsis often leads to multiple organ failure, with the NF-κB signaling pathway playing a pivotal role in this pathophysiological process (Fig.1). In the canonical NF-κB pathway, sepsis-inducing factors such as lipopolysaccharide (LPS) initiate downstream signaling cascades by activating Toll-like receptors (TLRs), ultimately resulting in the activation and nuclear translocation of NF-κB. The activated NF-κB promotes the transcription of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), thereby exacerbating the systemic inflammatory response. Furthermore, NF-κB regulates apoptosis and immune cell activation, playing a critical role in the progression of sepsis. In contrast, the non-canonical NF-κB pathway employs a distinct activation mechanism, typically in response to specific stimuli or in certain cell types, and involves different kinases, co-factors, and NF-κB subunit combinations.

Furthermore, cytokines such as interferon-gamma (IFN-γ) or interleukin-6 (IL-6) bind to cell surface receptors, leading to the activation of Janus kinases (JAKs), which in turn phosphorylate signal transducer and activator of transcription (STAT) proteins. The transport and activation mechanisms of the JAK/STAT signaling pathway play a crucial role in the pathophysiology of sepsis (Fig.2). These phosphorylated STAT proteins form dimers and translocate to the nucleus, where they regulate the expression of genes involved in inflammation, cell survival, and differentiation. Aberrant activation of the JAK/STAT pathway can drive disease progression, impair immune cell function, and lead to tissue damage and organ dysfunction.

In the dual-signaling model, the activation of the NLRP3 inflammasome involves a two-step process (Fig.3). The first step is the priming signal, where pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) upregulate the expression of NLRP3. The second step is the activation signal, wherein NLRP3 is activated by intracellular events such as potassium efflux and lysosomal rupture. The activated NLRP3 then binds to the apoptosis-associated speck-like protein containing a CARD (ASC) and pro-caspase-1, forming the inflammasome complex. This complex, in turn, promotes the maturation and release of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and interleukin-18 (IL-18), by cleaving pro-caspase-1 into its active form, caspase-1.

Within the unique inflammatory milieu of sepsis, characterized by both normoxic and hypoxic conditions, the mechanism of action of hypoxia-inducible factor 1-alpha (HIF-1α) differs (Fig.4). Under hypoxic conditions, the stability and activity of HIF-1α are significantly enhanced, leading to the activation of downstream signaling pathways that influence inflammatory regulation, immune responses, and organ dysfunction. HIF-1α not only directly regulates the expression of inflammatory genes but also interacts with the nuclear factor-kappa B (NF-κB) signaling pathway. As a pivotal inflammatory regulator, NF-κB also plays a crucial role in sepsis. During the onset and progression of sepsis, the activation of NF-κB results in the excessive production of inflammatory mediators.

Finally, as the primary energy generators of the cell, mitochondria rely on tightly regulated mechanisms to maintain their function (Fig.5). Fatty acid oxidation (FAO) is a critical energy-producing pathway within mitochondria; however, it is suppressed during sepsis, leading to insufficient energy production. Mitochondrial transcription factor A (TFAM) is essential for maintaining mitochondrial genome stability and regulating its transcription. In sepsis, however, the expression and function of TFAM may be impaired, which adversely affects mitochondrial biogenesis. Furthermore, nuclear respiratory factor (NRF) is a key transcription factor for mitochondrial biogenesis, and its activity is stimulated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master regulator of energy metabolism. PGC-1α enhances the activity of NRF, thereby promoting mitochondrial biogenesis and oxidative phosphorylation in response to energy demands. During sepsis, the expression and activity of PGC-1α are reduced, resulting in diminished mitochondrial biogenesis, which in turn exacerbates mitochondrial dysfunction and cellular damage.

Future prospects：

Sepsis represents a major global health challenge, characterized by immune dysregulation, metabolic disturbances, and organ dysfunction, with high mortality rates. Current research challenges include an insufficient understanding of the interactions among signaling pathways and their roles across pathological stages, as well as difficulties in clinical translation. Future efforts should focus on elucidating pathway crosstalk mechanisms, developing personalized targeted therapies, and screening biomarkers to enable precise patient stratification and intervention, thereby improving clinical outcomes.