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Introduction

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 and sepsis-induced inflammation

SIRT1 and inflammatory cells

Inflammatory cells, including macrophages (MQs), dendritic cells (DCs) and neutrophils (NEUs), play a pivotal role in the inflammatory response. As a deacetylase, SIRT1 modulates the secretion of inflammatory cells, influencing their differentiation, activation and maturation (5). SIRT1 can inhibit the activation of nuclear transcription factor-κB (NF-κB) by promoting the deacetylation of Akt, a serine/threonine kinase, thereby decreasing the production of pro-inflammatory cytokines and alleviating macrophage inflammation. Conversely, the absence of SIRT1 leads to excessive acetylation of Akt, exacerbating inflammatory cytokine production by MQs and promoting sepsis progression (9). SIRT1 is also involved in the inflammatory signaling of DCs, regulating the balance between type 1 T helper cells and regulatory T cells (10). DCs with SIRT1 knockout inhibit regulatory T cell generation and promote type 1 T helper cell development, leading to an enhanced T cell-mediated inflammatory response against pathogens (11). A study found that SIRT1-deficient murine model has reduced neutrophil infiltration at the infection site, an immature phenotype shift in NEUs and a decrease in the number of myeloperoxidase-positive NEUs, which have been hypothesized to lead to impaired neutrophil function and pathogen clearance (12).

SIRT1 and inflammatory mediators

Inflammatory mediators are pivotal in the development of sepsis owing to their role in pathogen clearance; however, their overactivation may lead to severe pathological outcomes (13). Research indicates that SIRT1 plays a significant role in regulating inflammatory mediators, with its activation or enhanced expression effectively mitigating inflammation and exerting anti-inflammatory effects (14,15). Tumor necrosis factor α (TNF-α), a pleiotropic pro-inflammatory cytokine produced by MQs and monocytes, generates a critical cytokine storm in sepsis and its levels are highly elevated (~10-fold compared with healthy individuals) in sepsis patients (16). SIRT1 reduces TNF-α secretion by deacetylating the NF-κB p65 subunit, thereby inhibiting TNF-α-induced NF-κB transcriptional activation. Furthermore, SIRT1 overexpression markedly decreases the levels of the pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, TNF-α and monocyte chemoattractant protein-1, alleviating lipopolysaccharide (LPS)-induced inflammation and organ damage (17).

SIRT1 and inflammatory signaling pathways

SIRT1 negatively regulates inflammatory response via various signaling pathways, particularly the NF-κB pathway. NF-κB, a heterodimer consisting of p50 and p65 subunits, exists in an inactive form in the cytoplasm and typically binds to the IκB subunit (18). IκB kinase (IKK) catalyzes the phosphorylation and subsequent degradation of the IκB subunit, under the influence of various pro-inflammatory factors, including IL-1β, IL-6 and TNF-α. This allows the NF-κB complex to be released and rapidly translocated into the nucleus, where it regulates the expression of inflammation-related genes (19). Studies have shown that SIRT1 inhibits the transcriptional activity of NF-κB by deacetylating lysine (Lys)-310, a key site of the NF-κB p65 subunit, thereby playing an anti-inflammatory role (20,21). SIRT1 can also inhibit IKK activity, subsequently inhibiting IκB degradation, thereby alleviating LPS-induced inflammation (22). In addition to confining the NF-κB complex within the cytoplasm, SIRT1 impairs its interaction with coactivators and RNA polymerase II, thus inhibiting gene transcription. Moreover, SIRT1 indirectly inhibits NF-κB signaling by modulating the expression of mediator proteins, including high mobility group box 1 (HMGB1), adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors (23,24). A decrease or absence of SIRT1 activity increases NF-κB activity, further promoting inflammation (25). These findings highlight the intricate interplay between SIRT1 and the NF-κB signaling pathway in modulating inflammatory response.

In sepsis, pathogenic microorganisms or endogenous molecules activate NF-κB, promoting NOD-like receptor protein 3 (NLRP3) inflammasome formation and pro-IL-1β expression (26). Activation of NLRP3 inflammasome further activates caspase-1, promoting the secretion of mature pro-inflammatory cytokines, such as IL-1β, IL-18, TNF-α and transforming growth factor-β. In addition to enhancing the inflammatory response, these factors recruit immune cells to the infection site and modulate the activity of adaptive immune cells (27). However, excessive activation of the NLRP3 inflammasome can lead to an uncontrolled inflammatory response (28). Guo et al (29) found that upregulating SIRT1 expression and activity can induce NF-κB deacetylation, inhibiting NLRP3 inflammasome-associated transcription factors and decreasing inflammasome assembly and activation in a sepsis murine model. This reduction in inflammasome activity decreases the maturation and secretion of IL-1β and IL-18, improving myocardial inflammatory status and decreasing myocardial cell apoptosis and damage.

Activator protein-1 (AP-1) is a key transcription factor (TF) in the inflammatory response and is composed of c-Jun and c-Fos proteins. SIRT1 can deacetylate specific Lys residues (such as Lys271) of the c-Jun protein, decreasing AP-1 activity and subsequently inhibiting the expression of inflammatory genes. Additionally, SIRT1 may indirectly regulate AP-1 activity by affecting other signaling pathways, including the mitogen-activated protein kinase pathway, further affecting the inflammatory response (23).

SIRT1 and non-coding RNAs in sepsis

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).

Role of SIRT1 in metabolism during sepsis

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.

Role of SIRT1 in oxidative stress (OS) during sepsis

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 and ERS in sepsis

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 and programmed cell death in sepsis

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.

SIRT1 and autophagy

In autophagy, intracellular materials or pathogens are engulfed by autophagosomes and degraded upon fusion with lysosomes (57). Autophagy plays a protective role by clearing pathogens, neutralizing microbial toxins, regulating cytokine release, decreasing target cell apoptosis and promoting antigen presentation (58). SIRT1 exerts multifaceted regulation of autophagy in sepsis. In LPS-induced sepsis, recombinant human erythropoietin alters the expression of autophagy-related proteins, including microtubule-associated protein 1A/1B-light chain 3 (LC3) I/LC3-II and P62, through the SIRT1/AMPK pathway, activating autophagy to prevent hepatic cell apoptosis (59). Sun et al (60) demonstrated that SIRT1 enhances autophagy in renal tubular epithelial cells through p53 deacetylation, thereby mitigating acute kidney injury in a murine model of LPS-induced sepsis. Furthermore, the authors observed that acetylated p53 is more prone to bind with Beclin1, accelerating its ubiquitination-mediated degradation and inhibiting autophagy (60). Deng et al (61) found that SIRT1 promotes autophagy and mitigates septic kidney damage by deacetylating Beclin-1 at Lys430 and Lys437. SIRT1 activation has been shown to promote Beclin-1 deacetylation and enhance autophagy, thereby alleviating sepsis-induced myocardial damage (62,63). Wang et al (64) demonstrated that aquaporin 3 promotes LPS-induced autophagy in Caco-2 cells by modulating the SIRT1/p62 signaling pathway, thus alleviating sepsis-induced intestinal epithelial cell damage. Furthermore, the authors found that EX 527, a SIRT1 inhibitor, abrogated the effects of aquaporin 3 overexpression. A recent study showed that SIRT1 signaling plays a critical role in limiting the hyperactivation of the stimulator of interferon genes and NLRP3 inflammasome through endosomal-mediated mitophagy during sepsis-induced acute lung injury (65). These findings suggest that SIRT1 activators can stimulate autophagy and mitophagy, highlighting their potential use in sepsis treatment.

SIRT1 and apoptosis

Apoptosis, a critical component in sepsis pathogenesis, is regulated by multiple signaling pathways and exerts its effects in various organs. SIRT1 prevents apoptosis by mediating the deacetylation of downstream targets, including p53, NF-κB and FOXO1. p53 potently induces apoptosis and was identified as the first non-histone deacetylation substrate of SIRT1 (46). SIRT1 catalyzes the NAD+-dependent deacetylation of p53 at its C-terminal lysine 382 residue by cleaving the nicotinamide-ribose bond and transferring the acetyl group to co-substrates, thereby inhibiting its trans-activating capacity and suppressing transcription-dependent apoptosis mediated by p53 (66). SIRT1-mediated p53 deacetylation plays a significant role in reducing apoptosis in septic conditions, thereby contributing to the preservation of organ function (67). Lin et al (68) demonstrated that SIRT1 overexpression attenuates apoptosis in sepsis-induced cardiomyopathy models by modulating p53. In a murine model of sepsis-induced lung injury, Yang et al (69) demonstrated that matrine treatment elicited comparable therapeutic outcomes, which were mechanistically associated with SIRT1/p53 signaling pathway activation and subsequent inhibition of sepsis-associated cellular apoptosis. Notably, while SIRT1 has been shown to suppress transcription-dependent apoptosis mediated by p53, its potential role in suppressing or promoting p53-mediated transcription-independent apoptosis remains unknown. Yang et al (69) also revealed the anti-apoptotic role of the SIRT1/NF-κB pathway, wherein SIRT1 modulates the NF-κB pathway to regulate inflammatory cytokine secretion, thereby inhibiting apoptosis. Furthermore, SIRT1-mediated regulation of FOXO1 alleviates OS-induced apoptosis and mitochondrial dysfunction (70).

SIRT1 and pyroptosis

Pyroptosis is a form of programmed cell death that is primarily induced by inflammasome-mediated activation of caspase family proteins, which cleave gasdermin proteins, such as gasdermin D (71). Pyroptosis leads to the release of cellular contents and subsequent cell death by releasing the N-terminal active fragments of gasdermin proteins that form pores on the cell membrane (72). SIRT1 has been found to regulate pyroptosis by modulating NLRP3 inflammasome activity. A study found that quercetin upregulated SIRT1 expression and reduced NLRP3 inflammasome activation, thereby inhibiting pyroptosis in the target organs of a septic murine model (73). Jiao et al (74) showed that exosomal miR-30d-5p increased p65 acetylation and activated NF-κB by targeting and suppressing SIRT1 expression in MQs, leading to MQ pyroptosis, which is associated with sepsis-related pneumonia. SIRT1 can also activate PGC-1α through deacetylation, which in turn activates Nrf2, allowing it to enter the nucleus and promote the expression of antioxidant genes, thereby decreasing OS and pyroptosis (75).

SIRT1 and ferroptosis

Ferroptosis is a recently discovered form of cell death that is induced by iron-dependent lipid peroxidation (76) and its pathogenesis is closely related to that of sepsis (77). A study demonstrated that quercetin exerts an anti-ferroptotic effect by activating the SIRT1/p53/solute carrier family 7 member 11 signaling pathway to alleviate sepsis-induced myocardial injury both in vivo and in vitro (68). Additionally, quercetin inhibits ferroptosis by activating the SIRT1/Nrf2/GPX4 signaling pathway, providing significant protection against LPS-induced lung injury (78). Another study found that irisin suppresses ferroptosis in a cecal ligation and puncture murine model through the SIRT1/Nrf2 signaling pathway, reducing the extent of renal damage (79). Ferroptosis inhibition involves a decrease in malondialdehyde levels, increase in glutathione levels to inhibit lipid peroxidation, decrease in hepatic iron content, increase in GPX4 expression and decrease in acetyl-CoA synthetase 4 expression (79).

Endothelial protective mechanism of SIRT1 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.

Conclusion and future perspectives

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.

Figure 1. The central regulatory role of SIRT1 in sepsis pathophysiology. SIRT1, a NAD+-dependent deacetylase, plays a pivotal role in modulating the pathophysiological processes in sepsis. SIRT1 initiates its anti-inflammatory action by deacetylating key proteins, such as Akt and NF-κB p65 subunit, which in turn suppress the activation of inflammatory signaling cascades and diminish the secretion of pro-inflammatory cytokines, leading to a regulated inflammatory response. Furthermore, SIRT1 attenuates oxidative stress by upregulating antioxidant enzymes and improving mitochondrial function, thereby reducing oxidative damage to cellular components. Metabolically, SIRT1 interacts with AMPK and PGC-1α, orchestrating a metabolic reprogramming that aligns with the energy requirements of immune cells, thus preserving immune-metabolic homeostasis. SIRT1 also safeguards cells from ERS-induced damage and modulates autophagy, a critical process for cellular homeostasis. Additionally, SIRT1 exerts its influence through p53/SLC7A11 pathways to inhibit both apoptosis and pyroptosis, which are significant contributors to tissue damage in sepsis. SIRT1, silent information regulator 1; NF-κB, nuclear transcription factor-κB; AMPK, adenosine monophosphate -activated protein kinase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1α; AP-1, activator protein-1; CAT, catalase; DC, dendritic cell; ERS, endoplasmic reticulum stress; FOXO, forkhead box O; GPX, glutathione peroxidase; HMGB1, high mobility group box 1; HO-1, heme oxygenase-1; IL-1β, interleukin-1β; IL-6, interleukin-6; MAPK, mitogen-activated protein kinase; NAD+, nicotinamide adenine dinucleotide; NLRP3, NOD-like receptor protein 3; Nrf2, nuclear erythroid 2-related factor 2; QOR, quinone oxidoreductase; ROS, reactive oxygen species; SLC7A11, solute carrier family 7 member 11; SOD, superoxide dismutase; Th1, type 1 T helper cells; Treg, regulatory T cells; TNF-α, tumor necrosis factor α.

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.

Acknowledgements

Not applicable.

Funding

The present study was supported by the Traditional Chinese Medicine research project of Chongqing Health Commission (grant no. 2022ZY7501), Chongqing Science and Technology Commission (grant no. CSTC2020JCYJ-MSXMX1069) and the Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau; grant no. 2024QNXM054).

Availability of data and materials

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Authors' contributions

QZ and WG were responsible for writing and editing the original draft. WZ was responsible for writing and reviewing the original draft and funding acquisition. ST was responsible for writing the original draft. HF was responsible for editing the manuscript. PP was responsible for writing, reviewing and editing the manuscript and supervision and funding acquisition. Data authentication is not applicable. All authors read and approved the final manuscript.

Ethics approval and consent to participate

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Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Authors' information

Dr Pengfei Pan: https://orcid.org/0000-0002-7024-3863

References