Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection (1), remains a significant global health burden despite the implementation of evidence-based clinical guidelines and notable advances in its treatment. The high mortality rate, prolonged hospital stay and substantial medical costs associated with sepsis (2,3) highlight the need for a deeper understanding of its complex and multifaceted pathogenesis. Furthermore, the mechanisms underlying its pathogenesis include immune dysregulation, complement system inactivation, mitochondrial damage, endoplasmic reticulum stress (ERS), autophagy, cell death and endothelial barrier disruption (4).

Silent information regulator 1 (SIRT1), a member of the sirtuins protein family, is a class III histone deacetylase that is dependent on nicotinamide adenine dinucleotide (NAD⁺). SIRT1 has been extensively studied for its role in sepsis and found to be involved in modulating gene expression and cellular processes (5). Moreover, the SIRT1-mediated deacetylation of both histone and non-histone proteins influences a wide range of cellular functions. Recent studies have shed light on the intricate regulatory mechanisms and signaling pathways modulated by SIRT1, offering new insights into the pathophysiological processes of sepsis (6,7). Research has demonstrated that SIRT1 plays a crucial role in the inflammatory response, oxidative damage, apoptosis and metabolic dysregulation associated with sepsis (8).

The present review focused on elucidating the role of SIRT1 in sepsis pathogenesis based on the recent advances in the understanding of the potential regulatory mechanisms and associated signaling pathways of SIRT1 in sepsis. Additionally, it aimed to provide new insights into the pathophysiological processes of sepsis and explore potential novel therapeutic strategies.

SIRT1 has been found to interact with various non-coding RNAs, including long non-coding RNAs, microRNAs (miRNAs/miR) and circular RNAs, thereby affecting sepsis development (6). Growth arrest-specific 5 (GAS5), which acts as a miR-155-5p sponge, promotes the expression of SIRT1 in patients and murine models with sepsis. Additionally, GAS5 alleviates cellular inflammatory responses by inhibiting excessive acetylation and release of HMGB1 (7). Zou et al (30) found that under sepsis conditions, increased connexin 43 expression (Cx43) leads to enhanced intercellular miR-181b transfer, affecting the SIRT1/forkhead box O3a (FOXO3a)-signaling pathway and subsequently causing cell and tissue damage. Cx43 inhibitors can inhibit the SIRT1/FOXO3a signaling pathway by regulating the intercellular transfer of miR-181b, thereby mitigating organ damage during sepsis (30). Circular RNA vesicle-associated membrane protein-associated protein A targets miR-212-3p to negatively regulate the expression of SIRT1 and cell pyroptosis-related factors, including nuclear erythroid 2-related factor 2 (Nrf2) and NLRP3 and inhibit LPS-induced cell pyroptosis and type 17 T helper cell-related inflammatory responses, which are involved in alleviating inflammatory damage in sepsis-induced acute lung injury (31). Additionally, SIRT1 has shown potential for inhibiting inflammation and the expression of cyclooxygenase-2 and inducible nitric oxide synthase by targeting the p53/miR-22 axis (32).

Metabolism is a fundamental physiological process that sustains growth, reproduction and normal functions in a living organism. Patients with sepsis frequently exhibit a series of acute responses, including tachycardia, fever, tachypnea, as well as activation of the immune, coagulation and complement systems, accompanied by a significant imbalance of energy metabolism (33). Glycolysis, glycogenolysis and lipolysis, along with accelerated fatty acid oxidation, lead to the breakdown of muscle tissue proteins, promoting a cachectic state (34). As immune cells compete with pathogens for glucose during their function execution, the disruption of glycolysis can impair the phagocytic and bactericidal capabilities of immune cells (35).

SIRT1 regulates glucose metabolism, lipid metabolism and mitochondrial quality control by forming a complex sensing network with various sensing proteins, such as AMPK, forkhead box protein O1 (FOXO1) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) (36). During sepsis, SIRT1 promotes a transition from a high-inflammatory stage characterized by glycolysis to a low-inflammatory stage characterized by fatty acid oxidation, by regulating metabolic pathways to meet the energy demands of immune cells and maintaining the balance between immune function and metabolism (37). However, persistent SIRT1 overexpression may suppress immune function and hinder infection foci clearance, ultimately resulting in energy exhaustion and organ dysfunction (38). Stark et al (39) found that SIRT1 can directly act on key rate-limiting glycolytic enzymes, including hexokinase 2, platelet-type phosphofructokinase and M2-type pyruvate kinase, to regulate the glycolytic process in endothelial cells, which may affect host's immunity against pathogens during sepsis. However, research on the effect of SIRT1 on energy metabolism and its potential regulatory mechanisms during sepsis remains limited, necessitating further in-depth exploration.

OS results from an imbalance between reactive oxygen species (ROS) production and the antioxidant defense system (40) and is a key factor in cellular damage. In the pathophysiology of sepsis, OS and inflammation reciprocally amplify each other, driving a self-perpetuating cycle that exacerbates tissue injury and systemic immune dysfunction. ROS, encompassing superoxide anions (O₂⁻), hydrogen peroxide (H₂O₂) and hydroxyl radicals (•OH), serve dual roles as both initiators and enhancers of inflammatory cascades. Mechanistically, IKK undergoes oxidation by ROS, triggering sequential phosphorylation and proteasomal degradation of IκB (41). This molecular event facilitates nuclear translocation of NF-κB, subsequently upregulating transcription of pro-inflammatory mediators that orchestrate systemic inflammatory responses. ROS-mediated oxidation of mitochondrial DNA (mtDNA) or induction of mitochondrial permeability transition pore opening enables cytosolic mtDNA release, thereby activating the NLRP3 inflammasome (42,43). Activated NLRP3 promotes caspase-1-mediated cleavage of pro-IL-1β and pro-IL-18 into their bioactive forms, perpetuating inflammatory cascades. Additionally, ROS activate the p38 mitogen-activated protein kinase and c-Jun N-terminal kinase pathways, enhancing AP-1 transcriptional activity, which synergizes with NF-κB to potentiate pro-inflammatory gene expression (41). Conversely, inflammatory cytokines exacerbate OS through multiple mechanisms. For instance, TNF-α and IL-1β enhance NADPH oxidase activity while suppressing antioxidant defense systems and disrupting mitochondrial electron transport chain integrity, collectively resulting in pathological ROS overproduction (44).

Numerous studies have indicated that SIRT1 plays a pivotal role in modulating OS processes during sepsis by regulating OS-related signaling pathways and gene expression. The multifaceted mechanisms underlying the SIRT1/AMPK signaling pathway are involved in alleviating OS, maintaining mitochondrial function and enhancing cellular resistance to OS. A study found that quercetin (a SIRT1 agonist) can bind to SIRT1 to elevate intracellular NAD⁺ levels and activate antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT), thus facilitating in reducing intracellular ROS levels and alleviating OS (45). SIRT1 can also directly improve mitochondrial function by deacetylating and activating AMPK, decreasing ROS production and promoting mitochondrial biogenesis, thus maintaining mitochondrial integrity and function. Furthermore, activated AMPK enhances fatty acid oxidation and increases intracellular adenosine triphosphate production, thus improving cellular resistance to OS. SIRT1 regulates members of the FOX family, including FOXO1, thereby promoting the expression of antioxidant enzymes, like SOD and CAT, consequently decreasing OS-induced cellular damage (46). Zhu et al (47) found that SIRT1 reduces malondialdehyde concentrations and increases SOD and CAT activities through the SIRT1/FOXO1 pathway, thus alleviating OS and protecting against sepsis-related brain cell damage. Similarly, SIRT1-mediated regulation of FOXO3 and FOXO4 helps mitigate OS response (48,49). Moreover, SIRT1 activation can inhibit NF-κB activity, alleviating OS injury in sepsis hepatocytes (50). One study showed that the SIRT1/NF-κB signaling pathway is involved in alleviating LPS-induced OS and subsequent renal damage in mice (51). SIRT1 activates p53-encoded antioxidant enzyme-related genes, such as SOD and GPX, to neutralize ROS, protecting cells from OS injury. Simultaneously, SIRT1 inhibits p53 activity by deacetylation, thereby decreasing the expression of oxidative factors and enhancing cell resistance to OS (52). Nrf2 is a leucine zipper TF that directly modulates the expression of antioxidant genes. Deacetylation of Nrf2 by SIRT1 promotes its binding to antioxidant response elements, enhancing the expression of downstream antioxidant proteins, such as quinone oxidoreductase and heme oxygenase-1, effectively clearing excess ROS and alleviating OS-induced damage (53). In sepsis models, SIRT1 increases PGC-1α acetylation to enhance its activity, thereby strengthening mitochondrial function, decreasing OS and protecting neurons from OS-induced damage (54).

SIRT1 plays a significant role in ERS, which is a critical component of sepsis pathophysiology. ERS is closely related to several important processes, including inflammatory responses, immune cell dysfunction and apoptosis (55). A study has shown that increased SIRT1 expression can markedly suppress ERS response in lung tissues and MQs through the protein kinase R-like ER kinase/eukaryotic initiation factor 2 α/activating TF 4/C/EBP homologous protein signaling pathway, thereby alleviating sepsis-related lung injury and pulmonary inflammation (56). Moreover, quercetin can inhibit OS-mediated ERS by activating the SIRT1/AMPK signaling pathway, thus decreasing sepsis-induced acute lung injury (45).

SIRT1 mediates programmed cell death processes across various tissues and organs in sepsis via multiple mechanisms. SIRT1-mediated cell death includes autophagy, apoptosis, pyroptosis and ferroptosis. An understanding of the different types of cell death is essential for developing targeted therapeutic strategies that can effectively mitigate organ-specific damage in sepsis.

Damage to the endothelial glycocalyx is an essential component of sepsis pathology. It exacerbates inflammatory response and promotes the activation of the coagulation system, leading to vascular dysregulation and inducing endothelial cell apoptosis (80). An increase in NAD⁺ (a SIRT1 substrate) levels can lead to the activation of the deacetylation function of SIRT1. A recent study found that combination therapy with interferon-β and nicotinamide riboside (as a SIRT1) effectively alleviated sepsis-induced vascular endothelial injury in an LPS-induced sepsis model (81). However, this protective mechanism was markedly weakened in a model with SIRT1 knockout endothelial cells, indicating the essential role of SIRT1 in maintaining vascular endothelial integrity. This study also revealed that SIRT1 can regulate the SIRT1/heparanase 1 pathway, contributing to the repair of damaged endothelial glycocalyx.

As illustrated in Fig. 1, SIRT1 modulates various signaling pathways and mechanisms and regulates inflammation, immune function, cellular metabolism, autophagy, apoptosis, pyroptosis and ferroptosis in sepsis. Moreover, SIRT1 exerts anti-inflammatory, anti-apoptotic and cytoprotective effects, making it a promising therapeutic target for sepsis.

Researchers have discovered and developed a range of SIRT1 agonists and antagonists, providing valuable insights into potential avenues for future research (82). Several strategies can be employed to ensure effective delivery of SIRT1-based drugs: i) Employing mononuclear-MQ cells as carriers for SIRT1 drugs; ii) employing target-specific nanotechnology-driven delivery systems; iii) administering SIRT1 modulators, such as resveratrol and quercetin; iv) activating signaling pathways, such as the AMPK signal pathway, to modulate autophagy and mitochondrial autophagy; and v) employing miRNA sponge technology to boost SIRT1 expression in targeted cells or organs. These approaches establish a foundation for the targeted administration of SIRT1-based therapies to address sepsis-induced organ dysfunction.

Despite significant progress in in vitro and in vivo experiments, our understanding of the regulatory mechanisms of SIRT1 in sepsis remains unclear. Most studies are focused on the role of SIRT1 in a single target organ and clinical trial data for SIRT1 modulators are extremely scarce, which limits the comprehensive understanding of the role of SIRT1 in sepsis (83,84). To address these limitations, future research should delve deeper into the regulatory mechanisms of SIRT1 in sepsis using a multidisciplinary approach combining advanced techniques, such as genomics, proteomics and metabolomics, to fully elucidate these mechanisms (85). Using the findings of these studies, more specific and effective SIRT1 modulators can be developed, providing new strategies for the prevention and treatment of sepsis.