Abstract
Sepsis-associated acute kidney injury (SA-AKI) is a severe complication of sepsis characterized by dysregulated inflammation, endothelial injury, and metabolic reprogramming. Among the numerous inflammatory mediators involved, S100 calcium-binding protein A12 (S100A12), a neutrophil-derived alarmin, has emerged as a key amplifier of receptor for advanced glycation end-products (RAGE) and toll-like receptor 4 (TLR4) signaling in this context. Through activation of these pathways, S100A12 drives inflammatory amplification, promotes cytokine release, pyroptotic and apoptotic cell death, endothelial dysfunction, and impaired tubular repair, thereby exacerbating renal injury. Experimental studies demonstrate that inhibition of S100A12 or blockade of its downstream signaling attenuates inflammation and tissue damage, whereas clinical evidence associates elevated circulating and urinary S100A12 levels with disease severity and adverse prognosis in sepsis. Collectively, current evidence positions S100A12 as both a mechanistic driver of inflammatory and metabolic reprogramming and a clinically actionable biomarker in SA-AKI. This review summarizes recent advances in the molecular biology and immunometabolic roles of S100A12 in SA-AKI, emphasizes its systemic versus kidney-specific effects, and discusses its translational potential as a biomarker and therapeutic target, highlighting opportunities and challenges for precision diagnostics and targeted therapies in sepsis-related organ injury.
1 Introduction
Sepsis-associated acute kidney injury (SA-AKI) is one of the most severe complications of sepsis, affecting up to half of critically ill patients and contributing substantially to morbidity and mortality (Gomez et al., 2014; Wang et al., 2021; Zarbock et al., 2023a). Despite advances in supportive care, the mortality of SA-AKI remains unacceptably high, often exceeding 50% (Kuwabara et al., 2022). Unlike other etiologies of acute kidney injury, SA-AKI arises from a complex interplay among dysregulated inflammation, microvascular dysfunction, and cellular metabolic reprogramming rather than from isolated ischemic or nephrotoxic insults (Cao et al., 2019; Hato and Dagher, 2025). These features complicate early diagnosis and limit the performance of conventional renal biomarkers, delaying timely therapeutic intervention (Zhu et al., 2021; Zarbock et al., 2023a; Hariri and Legrand, 2025).
S100 calcium-binding protein A12 (S100A12), a neutrophil-derived alarmin, has recently emerged as a key mediator and biomarker of inflammatory disorders. Through activation of the receptor for advanced glycation end-products (RAGE) and toll-like receptor 4 (TLR4), S100A12 amplifies innate immune signaling, promotes pyroptosis and apoptosis, impairs endothelial and tubular repair, and thereby exacerbates renal injury (Vallés et al., 2023; Zhou et al., 2023; Cross et al., 2024; Lin S. et al., 2025; Wang et al., 2025). Accumulating experimental and clinical evidence demonstrates that S100A12 levels are markedly elevated in sepsis, correlate with the severity of renal dysfunction, and may enable earlier detection of SA-AKI compared with conventional markers such as serum creatinine (He et al., 2024; Ostermann et al., 2024; Dubois, 2019). Moreover, preclinical studies indicate that inhibition of S100A12 signaling attenuates renal damage, highlighting its potential as a therapeutic target (Liliensiek et al., 2004; Kim C. H. et al., 2023; Vallés et al., 2023; Xia et al., 2024).
Given its dual role as both a mechanistic driver and a measurable biomarker, S100A12 represents a promising molecular link between innate immune activation and kidney injury in sepsis (Lin S. et al., 2025; Wu F. et al., 2025). This review summarizes current knowledge of S100A12 biology, its mechanistic contributions to the pathogenesis of SA-AKI, and its translational potential as a diagnostic and therapeutic target. In addition, it outlines key challenges and future directions required to translate these findings into clinical practice, including biomarker validation, mechanistic studies linking S100A12 to pyroptosis and immune signaling, and preclinical-to-clinical therapeutic development (e.g., small-molecule modulators or pathway blockade) (Lake et al., 2023; Ostermann et al., 2024; Yang et al., 2024; 2025). Notably, S100A12 is primate-specific; murine models therefore rely on transgenic or humanized S100A12 expression systems, which should be considered when interpreting experimental data.
2 Biology of S100A12
2.1 Structure and expression
Structurally, S100A12 is a small EF-hand calcium-binding protein that exerts multiple context-dependent functions. Also referred to as calgranulin C, it belongs to the S100 family of calcium-binding proteins and contains canonical EF-hand motifs (Moroz et al., 2001; Pietzsch and Hoppmann, 2009). This protein, with a molecular mass of approximately 10.4 kDa, comprises two EF-hand domains separated by a hinge region and a flexible, hydrophobic C-terminal tail (Moroz et al., 2003; Carvalho et al., 2020). The EF-hand domains coordinate divalent cations, most notably calcium (Ca2+) and zinc (Zn2+), which induce conformational rearrangements facilitating receptor interaction and oligomerization (Wang et al., 2019; Carvalho et al., 2020). Calcium binding promotes dimerization or higher-order oligomerization (e.g., tetramers, hexamers), essential for high-affinity receptor engagement—particularly with RAGE (Moroz et al., 2003; Wang et al., 2019).
S100A12 expression is largely restricted to cells of the myeloid lineage, with neutrophils serving as the predominant source, while monocytes and selected epithelial and endothelial cells express lower but inducible levels under inflammatory conditions (Lira-Junior et al., 2020; Li et al., 2022; Cross et al., 2024). During acute and chronic inflammation, transcriptional upregulation and extracellular release of S100A12 are markedly increased, and circulating concentrations correlate with disease activity and severity across conditions such as sepsis, autoimmune disease, and cardiovascular disorders (Xia et al., 2023). Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1β) enhance S100A12 expression via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)–dependent transcriptional activation through CCAAT/enhancer-binding protein-beta (C/EBPβ) and activator protein-1 (AP-1) motifs (Ott et al., 2007; Li et al., 2014).
S100A12 is secreted via non-classical pathways and acts extracellularly as a damage-associated molecular pattern (DAMP). Its primary receptor is RAGE, though TLR4 is also implicated (Zhou et al., 2023; Cicchinelli et al., 2024). RAGE engagement activates mitogen-activated protein kinase (MAPK) and NF-κB cascades, amplifying leukocyte recruitment, cytokine release, and endothelial activation (Zhang et al., 2024; Xia et al., 2023). In SA-AKI, the S100A12–RAGE axis promotes endothelial dysfunction, oxidative stress, and tubular apoptosis, linking neutrophil activation to maladaptive renal inflammation (Aguilar et al., 2024; Qin et al., 2024).
Emerging evidence highlights the regulatory role of post-translational modifications (PTMs) and metal-ion interactions in fine-tuning S100A12 function. Zn2+ binding enhances oligomer stability and receptor affinity (Moroz et al., 2009), whereas oxidative modifications alter its extracellular activity under septic and inflammatory conditions (Foell et al., 2007; Goyette and Geczy, 2011). Collectively, these findings suggest that S100A12 acts as a dynamic molecular switch integrating neutrophil activation, oxidative stress, and microenvironmental cues, rather than a static pro-inflammatory mediator (Cicchinelli et al., 2024). Collectively, these structural features endow S100A12 with remarkable metal-ion-dependent conformational flexibility that underlies its biological activity. Notably, S100A12 is primate-specific; murine investigations therefore rely on transgenic or humanized models.
To better illustrate these molecular features, Figure 1 summarizes the overall domain organization of S100A12 and highlights how Ca2+ and Zn2+ cooperatively stabilize its oligomeric states and enable receptor engagement.
FIGURE 1
2.2 Mechanisms in inflammation and immunity
S100A12 orchestrates multiple aspects of the inflammatory cascade in SA-AKI through interconnected mechanisms.
2.2.1 NF-κB activation via RAGE
Binding of S100A12 to RAGE on tubular epithelial and endothelial cells activates MAPK and NF-κB pathways, inducing the transcription of pro-inflammatory cytokines such as IL-1β, interleukin-6 (IL-6), and TNF-α. This axis sustains inflammatory amplification and paracrine injury within the renal microenvironment (Tanaka et al., 2019; Curran and Kopp, 2022; Dong et al., 2022; Kang et al., 2025).
2.2.2 TLR4/MyD88 engagement
Independent of RAGE, S100A12 can act as an endogenous ligand for TLR4. Engagement of TLR4 triggers myeloid differentiation primary response 88 (MyD88)-dependent signaling, resulting in NF-κB translocation and enhanced cytokine production, thereby amplifying monocyte activation and systemic inflammation (Foell et al., 2013; Jung et al., 2020; Kim H.-J. et al., 2023, p. 4).
2.2.3 Leukocyte recruitment
S100A12 possesses chemoattractant activity, promoting the recruitment and activation of neutrophils and monocytes. This leads to local immune cell accumulation, tubular epithelial cytotoxicity, and perpetuation of inflammatory damage (Yang et al., 2001; Rouleau et al., 2003; Yan et al., 2008; Meijer et al., 2012).
2.2.4 Pyroptosis via NLRP3 inflammasome
SA-AKI is characterized by robust NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation, leading to caspase-1 activation, gasdermin D cleavage, and pyroptotic cell death. S100A12 signaling primes NF-κB for enhanced NLRP3 assembly, promoting IL-1β and interleukin-18 (IL-18) release and exacerbating renal inflammation. Although direct in vivo and in vitro evidence for S100A12-induced NLRP3 assembly remains limited, multiple studies have demonstrated that other S100 family members, particularly heterodimer of S100A8 and S100A9 (S100A8/A9), can prime the NLRP3 inflammasome through TLR4/NF-κB or reactive oxygen species (ROS)-dependent pathways. Thus, it is reasonable to infer a comparable mechanism for S100A12, by analogy to other S100 proteins (e.g., S100A8/A9) (Liu et al., 2022; 2024; Zhang et al., 2023; Kodi et al., 2024; Wu W. et al., 2025).
2.2.5 Apoptosis via caspase-3
S100A12 promotes tubular epithelial apoptosis via caspase-3 activation, compromising epithelial integrity and renal function in SA-AKI (Hofmann Bowman et al., 2011). Experimental evidence from in vitro and in vivo models indicates that S100A12 can upregulate Fas and trigger caspase-3–dependent cell death, while clinical data show elevated soluble extracellular newly identified RAGE-binding protein (EN-RAGE) levels in sepsis and SA-AKI patients correlating with renal dysfunctions (Daffu et al., 2013; Cross et al., 2024; Kang et al., 2025). Together, these in vitro/in vivo and clinical observations support a role for S100A12 in both inflammatory amplification and tubular epithelial injury, highlighting its potential as a mechanistically relevant biomarker and therapeutic target.
2.2.6 Dysregulated autophagy
S100A12 may impair protective autophagy in tubular epithelial cells via NF-κB and inflammasome signaling, shifting stressed cells toward maladaptive death pathways such as pyroptosis and apoptosis (Zhao S. et al., 2023; Wu W. et al., 2025). This dysregulation of autophagy contributes to the loss of tubular integrity and exacerbates renal injury in SA-AKI (Zhang, 2024). Both experimental and clinical evidence support a role for S100A12 in modulating autophagic responses and promoting maladaptive cell death, highlighting its potential as a mechanistically relevant biomarker and therapeutic target (Chu et al., 2025). Collectively, these findings indicate that S100A12 contributes to the pathogenesis of SA-AKI through multiple interrelated inflammatory and immune mechanisms.
To provide a concise overview, the major signaling axes and downstream effects of S100A12 are summarized in Table1.
TABLE 1
| Mechanistic axis | Key pathway/Receptors | Molecular and cellular effects | Representative evidence | Pathophysiological outcome in SA-AKI |
|---|---|---|---|---|
| NF-κB activation via RAGE | S100A12–RAGE → MAPK/NF-κB | Upregulation of IL-1β, IL-6, TNF-α; sustained inflammatory amplification and paracrine injury within renal microenvironment | Foell et al. (2013),Curran and Kopp (2022),Dong et al. (2022),Kang et al. (2025) | Persistent cytokine storm, microvascular inflammation, and tubular damage |
| TLR4/MyD88 engagement | S100A12–TLR4 → MyD88-NF-κB axis | Activation of NF-κB, promotion of monocyte and macrophage inflammatory responses, amplification of systemic inflammation | (Yang et al., 2001; Jung et al., 2020; Kim H.-J. et al., 2023, p. 4) | Enhanced leukocyte activation and cytokine-driven renal inflammation |
| Leukocyte recruitment | S100A12 as chemoattractant | Chemotactic recruitment and activation of neutrophils/monocytes, induction of cytotoxicity toward tubular cells | (Rouleau et al., 2003; Yan et al., 2008; Meijer et al., 2012; Liu et al., 2022) | Immune cell infiltration, sustained tissue injury |
| Pyroptosis via NLRP3 inflammasome | S100A12 → NF-κB priming → NLRP3-caspase-1-GSDMD | Promotes IL-1β/IL-18 release, gasdermin D–mediated pore formation, and pyroptotic cell death; analogous to S100A8/A9 mechanisms | (Hofmann Bowman et al., 2011; Zhang et al., 2023; Kodi et al., 2024; Liu et al., 2024; Wu W. et al., 2025) | Exacerbated inflammatory cell death and renal tissue necrosis |
| Apoptosis via caspase-3 | S100A12 → Fas-caspase-3 pathway | Induces tubular epithelial apoptosis, loss of epithelial barrier integrity; elevated serum EN-RAGE correlates with renal dysfunction | (Daffu et al., 2013; Foell et al., 2013; Zhao S. et al., 2023; Cross et al., 2024) | Tubular epithelial loss, renal dysfunction |
| Dysregulated autophagy | S100A12 → NF-κB/inflammasome axis | Impairs protective autophagy, shifts toward pyroptosis/apoptosis under stress | (Hofmann Bowman et al., 2011; Cunden et al., 2016; Zhang, 2024; Chu et al., 2025) | Maladaptive cell death and worsening tubular injury |
Mechanistic roles of S100A12 in inflammation and immunity during sepsis-associated acute kidney injury (SA-AKI).
Abbreviations: SA-AKI, sepsis-associated acute kidney injury; S100A12, S100 calcium-binding protein A12; RAGE, receptor for advanced glycation end-products; TLR4, Toll-like receptor 4; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; MAPK, mitogen-activated protein kinase; IL, interleukin; TNF-α, tumor necrosis factor alpha; NLRP3, NOD-, LRR-, and pyrin domain-containing protein 3; GSDMD, gasdermin D; EN-RAGE, extracellular newly identified RAGE-binding protein; Fas, Fas receptor; ROS, reactive oxygen species; DAMPs, damage-associated molecular patterns.
2.3 Physiological and pathological roles
2.3.1 Role in innate immunity
Under physiological conditions, S100A12 contributes to antimicrobial defense as part of the innate immune response. Its calcium- and zinc-dependent conformational changes enable direct interaction with microbial components and regulation of neutrophil adhesion, migration, and degranulation (Cunden et al., 2016). Extracellularly, S100A12 acts as a DAMP, engaging receptors such as RAGE and TLR4 to amplify immune signaling, enhance leukocyte recruitment, and stimulate cytokine secretion (Xia et al., 2023). These functions underscore its dual role as both an antimicrobial effector and an immunomodulatory signal in innate immunity (Singh and Ali, 2022).
2.3.2 Contribution to systemic inflammation and tissue injury
While protective during localized infection, uncontrolled or sustained S100A12 release drives systemic inflammation. Elevated circulating levels of S100A12 are strongly associated with multi-organ dysfunction and poor outcomes in sepsis. Persistent activation of the S100A12-RAGE/TLR4 axis induces endothelial dysfunction, oxidative stress, and microvascular barrier disruption, thereby impairing tissue perfusion (Zhang, 2024). In the kidney, these processes promote tubular apoptosis, hinder reparative responses, and exacerbate inflammatory injury, contributing directly to SA-AKI pathogenesis (Arendshorst et al., 2024). Beyond the kidney, excessive S100A12 activity has been implicated in cardiovascular disease, autoimmune disorders, and other chronic inflammatory conditions, reflecting its broader role as a mediator of systemic tissue damage (Zhou et al., 2023).
3 Pathophysiological role of S100A12 in SA-AKI
S100A12 participates in multiple pathogenic processes of SA-AKI, including inflammatory amplification, endothelial dysfunction, cell death, and metabolic reprogramming (Figure 2).
FIGURE 2
3.1 Inflammatory amplification
3.1.1 Cytokine storm and neutrophil activation
SA-AKI is tightly linked to systemic hyperinflammation, in which S100A12 functions as a potent neutrophil-derived alarmin (Motomura et al., 2021). Upon release, S100A12 binds to the RAGE and TLR4, amplifying NF-κB–dependent cytokine production and driving a cytokine storm characterized by elevated IL-1β, IL-6, and TNF-α (Singh and Ali, 2022; Xia et al., 2023). This cascade perpetuates neutrophil activation, enhances degranulation, and aggravates renal injury (Motomura et al., 2021).
3.1.2 Cross-talk with macrophages and endothelial cells
S100A12 also mediates cross-talk among neutrophils, macrophages, and endothelial cells. By activating macrophages, it promotes inflammasome priming and IL-18 release, further amplifying renal inflammation (Lenga Ma Bonda et al., 2022; Islamuddin and Qin, 2024). In parallel, S100A12 stimulates endothelial activation and upregulates adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), facilitating leukocyte adhesion and microvascular obstruction within the renal circulation (Kong et al., 2018; Haydinger et al., 2023, p. 1).
3.2 Microvascular dysfunction
3.2.1 Endothelial barrier disruption
The S100A12–RAGE axis promotes endothelial dysfunction by increasing ROS-dependent oxidative stress and suppressing tight-junction proteins, culminating in barrier failure (Rojas et al., 2024). The resulting vascular leakage and microcirculatory collapse impair renal perfusion, independent of systemic hypotension (McMullan et al., 2024).
3.2.2 Leukocyte adhesion and microcirculatory impairment
S100A12 enhances leukocyte rolling and adhesion within peritubular capillaries, aggravating microvascular congestion and impairing oxygen delivery (Yang et al., 2007). This imbalance between oxygen supply and metabolic demand contributes to the non-ischemic nature of SA-AKI (Sutton, 2009).
3.3 Cellular injury and death
3.3.1 Pyroptosis and apoptosis in renal tubular cells
At the tubular level, S100A12 promotes both pyroptosis and apoptosis. NF-κB–driven activation of the NLRP3 inflammasome induces caspase-1 cleavage, gasdermin D pore formation, and pyroptotic cytokine release. Concurrently, S100A12 signaling triggers caspase-3–dependent apoptosis, further compromising tubular epithelial integrity.
3.3.2 Impaired tubular repair and regeneration
Persistent S100A12 activation interferes with reparative signaling pathways (Xu et al., 2022). Excessive inflammation suppresses tubular proliferation and delays epithelial regeneration (Li et al., 2023), leading to incomplete recovery, progression to chronic kidney disease, and increased long-term morbidity (Lake et al., 2023).
3.4 Metabolic reprogramming
3.4.1 Mitochondrial dysfunction
Mitochondrial injury is a hallmark of SA-AKI (Zhang et al., 2021). S100A12 exacerbates mitochondrial ROS generation and disrupts electron transport chain activity, resulting in reduced adenosine triphosphate (ATP) production (Su et al., 2023). This metabolic stress accelerates tubular apoptosis and undermines adaptive repair mechanisms (Rashid et al., 2023).
3.4.2 Links between energy metabolism and kidney injury
Multi-omics studies reveal metabolic reprogramming as a defining feature of SA-AKI, characterized by suppressed fatty acid oxidation and disordered amino acid metabolism (Zhao L. et al., 2023). S100A12-driven inflammation may act synergistically with these metabolic derangements to aggravate energy deficits in tubular cells and heightening renal vulnerability to sepsis-induced injury (Wang et al., 2024).
3.5 Crosstalk between S100A12 and other DAMPs
Beyond its independent pro-inflammatory activity, S100A12 likely operates within a broader damage-associated molecular pattern (DAMP) network during sepsis and sepsis-associated AKI. Among these DAMPs, high-mobility group box 1 (HMGB1) is particularly relevant, as both S100A12 and HMGB1 are released during cellular stress and tissue injury and share key pattern-recognition receptors, including the RAGE and TLR4. Engagement of these shared receptors can converge on NF-κB and MAPK signaling pathways, leading to amplified cytokine production, endothelial activation, and sustained inflammatory responses (Rai et al., 2022; Cicchinelli et al., 2024).
Experimental studies in sepsis models suggest that DAMPs may act sequentially or synergistically, with early neutrophil-derived mediators such as S100A12 priming the inflammatory milieu, thereby enhancing cellular responsiveness to late mediators such as HMGB1. Although direct evidence for S100A12–HMGB1 cooperation in SA-AKI remains limited, this conceptual framework supports the notion that S100A12 functions as part of an integrated DAMP signaling network rather than as an isolated effector (Ludes et al., 2021; Huang et al., 2025; Lin H. et al., 2025).
3.6 Summary
Collectively, S100A12 acts as a central mediator linking systemic sepsis-induced inflammation to renal tissue injury (Ludes et al., 2021). By amplifying cytokine cascades, disrupting microvascular integrity, promoting tubular cell death, and exacerbating metabolic dysfunction, S100A12 contributes to both the onset and progression of SA-AKI (Kounatidis et al., 2024; Legrand et al., 2024; Zhang, 2024; Xia et al., 2023). These multifaceted effects underscore its dual role as a mechanistic driver of renal injury and a potential therapeutic and prognostic biomarker in sepsis-associated organ dysfunction.
4 Evidence from preclinical and clinical studies
4.1 Preclinical studies
Preclinical studies using transgenic mice that express human S100A12 (mice lack an endogenous S100A12 gene) demonstrate that, during sepsis, renal upregulation of human S100A12 is closely associated with tubular injury, neutrophil infiltration, and activation of pro-inflammatory pathways; genetic or antibody-mediated suppression of S100A12 attenuates apoptosis and improves renal function (Hofmann Bowman et al., 2010; Gawdzik et al., 2011; Bagheri, 2022). Complementary in vitro studies using human renal tubular epithelial cells and monocytes further corroborate these findings: small interfering RNA (siRNA)–mediated knockdown or antibody blockade of S100A12 significantly reduces lipopolysaccharide (LPS)-induced cytokine release and apoptosis (Foell et al., 2013; Zhang Z. et al., 2020).
4.2 Clinical observational studies
Clinical studies have confirmed these experimental findings, demonstrating that elevated circulating and urinary S100A12 levels are associated with both the presence and severity of SA-AKI (Dubois, 2019). In septic patient cohorts, plasma S100A12 concentrations were markedly higher in individuals who developed AKI and correlated with the degree of renal dysfunction (Wu et al., 2022). Notably, urinary S100A12 levels increased early during sepsis-preceding elevations in conventional renal biomarkers such as serum creatinine (Li et al., 2022). Furthermore, high S100A12 levels predicted worse outcomes, including increased mortality and the need for renal replacement therapy (Dubois, 2019), underscoring its potential as an early diagnostic and prognostic marker in septic patients.
4.3 Comparison with conventional biomarkers
Compared with established renal biomarkers such as serum creatinine, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1), S100A12 offers several key advantages. First, S100A12 rises early in the course of sepsis, allowing detection of renal injury before measurable changes in serum creatinine (Zhang C.-F. et al., 2020; Ortín-Bustillo et al., 2023). Second, its strong association with systemic inflammation and immune activation provides a mechanistic link between immune dysregulation and renal dysfunction, which conventional biomarkers lack (Wang et al., 2018; Seibert et al., 2021). Finally, studies indicate that S100A12 exhibits superior diagnostic performance, with higher sensitivity and specificity for predicting SA-AKI compared to NGAL and KIM-1 (Ortín-Bustillo et al., 2023; Brozat et al., 2024). These findings suggest that S100A12 may enable earlier clinical intervention and improved outcome stratification in patients with sepsis-related kidney injury.
4.4 Systemic versus kidney-specific effects of S100A12
An important unresolved issue is the distinction between systemic and organ-specific effects of S100A12 during sepsis (Raz, 2007). Circulating S100A12 primarily reflects systemic neutrophil activation and has been implicated in widespread endothelial dysfunction, microvascular injury, and cytokine amplification across multiple organs (Bertheloot and Latz, 2017; Cicchinelli et al., 2024). These systemic effects may indirectly contribute to renal hypoperfusion, inflammation, and susceptibility to acute kidney injury (Bertheloot and Latz, 2017; Lin H. et al., 2025).
In contrast, organ-specific effects within the kidney may arise from local interactions between S100A12 and renal tubular epithelial cells, glomerular or peritubular endothelial cells, and resident immune cells, potentially via RAGE- or TLR4-dependent signaling (Gustot, 2011; Lin H. et al., 2025). Such localized signaling could promote tubular inflammation, cell death, and metabolic dysfunction independently of systemic hemodynamic changes (Xie et al., 2013). However, current clinical and experimental studies often lack the spatial or temporal resolution required to clearly disentangle systemic from kidney-specific actions of S100A12 (Gustot, 2011; Cicchinelli et al., 2024). Future studies employing compartment-specific sampling, kidney-targeted experimental models, or spatial transcriptomic approaches may help clarify these distinct contributions (Cicchinelli et al., 2024).
5 Translational and therapeutic implications of S100A12 in SA-AKI
5.1 Diagnostic and prognostic value
5.1.1 Risk stratification in septic patients
S100A12 has emerged as a promising biomarker for early detection and risk stratification in SA-AKI. Elevated admission plasma S100A12 correlates with increased mortality and multi-organ dysfunction in septic patients; for example, Dubois et al. reported that higher S100A12 levels at presentation identified septic shock patients at greater risk of death (Dubois, 2019). In addition, combining S100A12 with other clinically used markers (e.g., cardiac enzymes) improves the prediction of sepsis-related cardiac injury, supporting its broader prognostic utility in critical illness (Wu F. et al., 2025).
5.1.2 Integration into biomarker panels
Integrating S100A12 into multi-analyte panels enhances early diagnosis and prognosis of SA-AKI. When used together with conventional renal biomarkers such as serum creatinine and NGAL, S100A12 increases sensitivity and specificity for detecting incipient renal injury, thereby enabling timelier intervention and risk-aligned management (Xie et al., 2021).
5.2 Therapeutic targeting of S100A12 pathways
5.2.1 Neutralizing antibodies and small-molecule inhibitors
Therapeutic strategies that neutralize S100A12 or modulate its activity show promise in SA-AKI. Quinoline-3-carboxamide derivatives (e.g., ABR-215757) have been identified as small-molecule inhibitors capable of attenuating S100A12-driven inflammation and organ injury in preclinical settings, supporting targetability of this pathway (Yan et al., 2013).
5.2.2 Modulation of RAGE/TLR4 signaling
S100A12 exerts pro-inflammatory effects primarily via the receptor for RAGE and TLR4. Pharmacologic interruption of these axes can blunt downstream signaling and tissue injury. FPS-ZM1, a high-affinity RAGE inhibitor, reduces inflammatory cytokine release and oxidative stress by blocking S100A12–RAGE interaction in experimental models (Shen et al., 2017). Likewise, interventions aimed at TLR4 signaling mitigate S100A12-initiated inflammatory cascades and have been proposed as a complementary strategy in SA-AKI (Vallés et al., 2023; Niu et al., 2024). Collectively, these findings support pharmacologic blockade of S100A12 and its downstream signaling as a rational and potentially translatable approach in SA-AKI. For comparison across modalities, major therapeutic strategies targeting the S100A12–RAGE/TLR4 axis are summarized in Table 2.
TABLE 2
| Therapeutic strategy | Target/mechanism of action | Representative agents/interventions | Experimental/clinical evidence | Observed or proposed effect in SA-AKI |
|---|---|---|---|---|
| Neutralizing antibodies and small-molecule inhibitors | Direct inhibition of S100A12 activity; blockade of ligand–receptor interaction | Quinoline-3-carboxamide derivatives (e.g., ABR-215757); S100A12-neutralizing antibodies | Preclinical studies demonstrate suppression of S100A12-mediated inflammation and organ injury in models of sepsis and autoimmunity (Shen et al., 2017) | ↓Pro-inflammatory cytokines (IL-1β, IL-6, TNF-α); ↓ oxidative stress; ↓ tissue injury |
| Modulation of RAGE signaling | Inhibition of S100A12-RAGE interaction; attenuation of downstream NF-κB/MAPK activation | FPS-ZM1 (high-affinity RAGE inhibitor) | Experimental data show FPS-ZM1 reduces inflammatory cytokine release and oxidative stress by preventing S100A12-RAGE binding (Niu et al., 2024) | ↓ Inflammatory amplification; ↓ microvascular dysfunction; protection of tubular epithelial cells |
| Modulation of TLR4 signaling | Suppression of S100A12-induced TLR4/MyD88-NF-κB axis | TLR4 antagonists (e.g., TAK-242, Eritoran) | Preclinical evidence supports inhibition of TLR4-dependent cytokine cascade and leukocyte activation (Ewaisha and Anderson, 2023; Vallés et al., 2023) | ↓ Systemic inflammation; ↓ renal cytokine burden; attenuation of tubular injury |
Representative therapeutic strategies targeting S100A12 and the downstream RAGE/TLR4 axis.
Abbreviations: SA-AKI, sepsis-associated acute kidney injury; S100A12, S100 calcium-binding protein A12; RAGE, receptor for advanced glycation end-products; TLR4, Toll-like receptor 4; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; MAPK, mitogen-activated protein kinase; IL, interleukin; TNF-α, tumor necrosis factor alpha; ROS, reactive oxygen species; DAMPs, damage-associated molecular patterns; ABR-215757, paquinimod; FPS-ZM1, RAGE, inhibitor; TAK-242, TLR4 inhibitor; Eritoran, TLR4 antagonist. Bold text highlights key inflammatory mediators or biological effects, and arrows indicate the direction of change.
5.2.3 Challenges and safety considerations
Despite encouraging signals, several issues warrant careful evaluation before clinical translation. Specificity and off-target effects of neutralizing antibodies and small-molecule inhibitors must be rigorously profiled to minimize unintended interactions and efficacy loss; long-term safety and durability also require confirmation in well-designed trials. Methodological frameworks that apply orthogonal assays to characterize off-target liabilities can strengthen safety assessment paradigms (Wang et al., 2025). Moreover, redundancy and compensation within inflammatory networks mean that targeting S100A12 (and related ligands such as S100A8/A9) or their receptors (RAGE/TLR4) should balance efficacy with preservation of essential host defenses, a principle underscored by experience in autoimmune indications (Ewaisha and Anderson, 2023).
6 Current challenges and knowledge gaps
Despite compelling preclinical and early clinical evidence supporting the role of S100A12 in SA-AKI, several key challenges limit its translational applicability and clinical implementation.
6.1 Heterogeneity of clinical studies
Existing studies on S100A12 in SA-AKI are highly heterogeneous regarding patient selection, sepsis etiology, sampling time-points, and outcome definitions. Many cohorts include mixed intensive care unit (ICU) populations with varying organ dysfunction, obscuring the specific contribution of S100A12 to renal injury. Endpoints are inconsistently defined—from biochemical AKI criteria (serum creatinine/urine output) to composite organ dysfunction scores—further reducing comparability and hindering meta-analytic synthesis (Zarbock et al., 2023b; Legrand et al., 2024). To enable clinical validation, future studies should adopt standardized, patient-centered outcomes, prespecified sampling windows, and multicenter cohorts incorporating subgroup and sensitivity analyses to address confounding and heterogeneity (Ortín-Bustillo et al., 2023; Baeseman et al., 2024; Wu F. et al., 2025).
6.2 Lack of large-scale, prospective validation
Most available evidence is derived from small, single-center, or retrospective cohorts, which restricts the evaluation of S100A12’s predictive value in early-stage SA-AKI and risk stratification. Well-designed, prospective, multicenter studies are required to establish clinically meaningful thresholds, quantify inter-individual variability, and assess reproducibility across diverse populations differing in age, comorbidities, and sepsis etiologies (Legrand et al., 2024; Llitjos et al., 2024). Moreover, rigorous studies should clarify the incremental value of S100A12 over established kidney injury markers such as NGAL, KIM-1, and the cell-cycle arrest biomarker pair tissue inhibitor of metalloproteinases-2 × insulin-like growth factor-binding protein 7 ([TIMP-2]·[IGFBP7]) (Baeseman et al., 2024; Ostermann et al., 2024). Without harmonized protocols and prospective data, reliable integration of S100A12 into clinical workflows remains challenging. Future research should prioritize multicenter, preregistered validation cohorts and randomized trial sub-studies to confirm predictive capacity, define actionable thresholds, and clarify additive value beyond conventional biomarkers.
6.3 Limitations in translating animal data to humans
Translational studies face a major biological limitation: S100A12 is primate-specific, and mice lack an endogenous ortholog, complicating direct extrapolation from conventional murine models to human SA-AKI. Humanized or transgenic mice expressing human S100A12 provide valuable tools for mechanistic exploration but remain technically demanding and not widely available (Foell et al., 2007; Oesterle and Hofmann Bowman, 2015). Furthermore, interspecies differences in immune composition, renal metabolism, and inflammatory signaling restrict the translation of preclinical interventions—such as soluble receptor for advanced glycation end-products (sRAGE) or inflammasome inhibitors—to human settings (Russo et al., 2021; Zarbock et al., 2023b). Bridging this gap will require integrating humanized animal models, kidney organoids, and multi-omics platforms to more accurately recapitulate human disease biology.
6.4 Need for standardized assays for S100A12 detection
Although commercial enzyme-linked immunosorbent assay (ELISA) kits allow quantification of S100A12 in plasma, serum, and urine, significant analytical and preanalytical variability limits reproducibility. Factors such as blood collection technique, anticoagulant type, centrifugation parameters, storage conditions, and freeze–thaw cycles significantly affect measured concentrations and contribute to inter-laboratory inconsistency (O’Bryant et al., 2015; Agrawal et al., 2018). Assays from different manufacturers also vary in calibration standards, antibody specificity, and sensitivity, and published data on intra- and inter-assay coefficients of variation lack harmonization (Andreasson et al., 2015). These inconsistencies reduce cross-study comparability and hinder inclusion of S100A12 in multimarker panels (Ortín-Bustillo et al., 2023). To facilitate multicenter validation and clinical translation, future studies should establish standardized, traceable assays linked to reference measurement procedures, harmonized preanalytical protocols, and external quality assessment (EQA) programs to ensure analytical reliability across laboratories.
6.5 Summary
Although S100A12 represents a promising biomarker and therapeutic target in SA-AKI, its clinical translation is currently constrained by multiple interrelated gaps: heterogeneity in study design and endpoints (Legrand et al., 2024), limited prospective multicenter validation (Llitjos et al., 2024), species-specific barriers to translation (Hofmann Bowman et al., 2011), and the absence of standardized detection protocols (Ng et al., 2025). Addressing these limitations will require: (i) large, prospective multicenter trials with harmonized outcome definitions and prespecified sampling windows; (ii) development and cross-validation of standardized assays with preanalytical standard operating procedures (SOPs) and external quality assessment (EQA); (iii) integration of S100A12 quantification into multi-omics and multimarker frameworks to clarify biological and clinical context; and (iv) improved translational platforms—such as humanized or organoid models—to enable mechanism-informed therapeutic development. Collectively, these coordinated efforts are essential for the reliable incorporation of S100A12 into precision diagnostic and therapeutic strategies for SA-AKI.
7 Perspectives
Despite growing evidence implicating S100A12 in the pathogenesis and progression of SA-AKI, emerging concepts now provide a roadmap for translating this knowledge into precision diagnostics and therapeutic interventions (Legrand et al., 2024; Llitjos et al., 2024).
7.1 Precision medicine and enrichment trials
S100A12 is a promising molecular biomarker for patient stratification in SA-AKI. Its dynamic expression reflects neutrophil activation, inflammasome signaling, and renal tubular injury, identifying patients with pronounced inflammatory and immune-driven phenotypes (Ortín-Bustillo et al., 2023; Wu F. et al., 2025). Incorporating S100A12 into enrichment trial designs may allow selection of sub-populations most likely to benefit from immunomodulatory or anti-inflammatory therapies, thereby reducing heterogeneity in treatment responses. Endotype-guided approaches, in which patients are stratified using biomarker panels including S100A12, NGAL, and [TIMP-2]·[IGFBP7], can optimize trial efficiency and enhance the detection of clinically meaningful effects in early-stage SA-AKI and high-risk septic shock cohorts (Legrand et al., 2024; Llitjos et al., 2024).
7.2 Multi-omics approaches to integrate S100A12 biology
Integration of S100A12 measurements with multi-omics datasets, including transcriptomics, proteomics, metabolomics, and single-cell immunophenotyping, provides a comprehensive perspective on its role in SA-AKI pathophysiology (He et al., 2024; Zhang, 2024). Machine learning applied to these data can identify molecular signatures associated with S100A12-driven pathways, such as RAGE-mediated NF-κB and PI3K/Akt activation, NLRP3 inflammasome priming, and metabolic reprogramming of renal tubular cells. Such integrated analyses may uncover novel druggable targets, enable early detection of renal injury, and guide personalized therapeutic interventions (He et al., 2024; Zhang, 2024).
7.3 Potential role in guiding immunomodulatory therapies
As a DAMP and potent amplifier of inflammatory cascades, S100A12 may serve as both a biomarker and a therapeutic target (Hofmann Bowman et al., 2011; Wu F. et al., 2025). Potential strategies include direct neutralization of S100A12, blockade of its receptor RAGE, or downstream inhibition of inflammasome and NF-κB signaling. Monitoring circulating S100A12 levels could also inform the timing and dosing of immunomodulatory therapies, allowing dynamic adjustments based on the patient’s inflammatory status. Combination strategies integrating metabolic modulation with immunotherapy may further enhance tubular resilience and improve renal outcomes in SA-AKI (Hofmann Bowman et al., 2011; Wu F. et al., 2025).
7.4 Future directions
Future research should prioritize: (i) prospective multicenter trials incorporating S100A12 for patient stratification; (ii) development of standardized, high-sensitivity assays for longitudinal monitoring; (iii) integration of S100A12 into multi-omics frameworks to clarify mechanistic links with tubular metabolism, inflammasome activation, and apoptosis; and (iv) preclinical testing in humanized or primate models to validate therapeutic targets. Collectively, these strategies have the potential to establish S100A12 as a cornerstone of precision-guided diagnostics and immunomodulatory therapy in SA-AKI.
8 Conclusion
S100A12 has emerged as a mechanistically informed and clinically relevant biomarker in SA-AKI. Its rapid induction in neutrophils and monocytes, coupled with engagement of RAGE/NF-κB and NLRP3 inflammasome pathways, links systemic inflammation to tubular injury, pyroptosis and apoptosis, and metabolic dysregulation (Legrand et al., 2024; Llitjos et al., 2024; Wu F. et al., 2025). Unlike conventional markers such as serum creatinine or blood urea nitrogen (BUN), S100A12 rises early, reflecting immune activation and renal inflammatory burden, offering potential for early detection, risk stratification, and monitoring of disease progression (Ortín-Bustillo et al., 2023; Legrand et al., 2024).
Preclinical evidence supports S100A12 as a therapeutic target; neutralization, RAGE blockade, or downstream pathway modulation can mitigate tubular injury, restore metabolic homeostasis, and improve survival in experimental sepsis models (Hofmann Bowman et al., 2011; Wu F. et al., 2025). Adjunctive strategies, including immunomodulation, metabolic preprogramming, and extracorporeal removal of alarmins, may further leverage the S100A12 axis to reduce organ dysfunction (He et al., 2024; Wu F. et al., 2025).
Clinical translation remains in its early stages. Large-scale, prospective studies are required to validate predictive and prognostic utility, standardize assays, and evaluate interventions targeting the S100A12-RAGE pathway. Integration into multi-omics analyses, precision medicine frameworks, and enrichment trial designs will be critical to identify patient subphenotypes most likely to benefit (Hofmann Bowman et al., 2011; Agrawal et al., 2018; Ortín-Bustillo et al., 2023; He et al., 2024; Legrand et al., 2024; Llitjos et al., 2024; Wu F. et al., 2025).
In conclusion, S100A12 represents a mechanistic nexus connecting systemic inflammation to kidney injury in sepsis. Its dual role as an early biomarker and potential therapeutic target positions it at the forefront of precision-guided strategies for SA-AKI, providing a translationally actionable path to improve early diagnosis, risk stratification, and patient outcomes. Future research should prioritize prospective multicenter validation, assay standardization, and mechanism-driven clinical trials to accelerate S100A12-guided interventions into practice.
Statements
Author contributions
HL: Writing – original draft, Conceptualization, Funding acquisition, Visualization, Data curation, Formal Analysis. YL: Writing – review and editing, Investigation, Validation. QX: Validation, Writing – review and editing. JS: Validation, Project administration, Methodology, Supervision, Writing – review and editing, Conceptualization, Funding acquisition.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by Key R&D Program of Jining (Grant No. 2023YXNS106) and the Shandong Province Medical and Health Science and Technology Development Project (Grant No. 202319010449).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Glossary
- AKI
acute kidney injury
- AP-1
activator protein-1
- ATP
adenosine triphosphate
- BUN
blood urea nitrogen
- C/EBPβ
CCAAT/enhancer-binding protein beta
- DAMP
damage-associated molecular pattern
- ELISA
enzyme-linked immunosorbent assay
- EN-RAGE
extracellular newly identified RAGE-binding protein
- ERK1/2
extracellular signal-regulated kinase 1/2
- ICAM-1
intercellular adhesion molecule-1
- ICU
intensive care unit
- IL-1β
interleukin-1 beta
- IL-6
interleukin-6
- IL-18
interleukin-18
- KIM-1
kidney injury molecule-1
- LPS
lipopolysaccharide
- MAPK
mitogen-activated protein kinase
- MyD88
myeloid differentiation primary response 88
- NGAL
neutrophil gelatinase-associated lipocalin
- NF-κB
nuclear factor kappa-light-chain-enhancer of activated B cells
- NLRP3
NOD- LRR- and pyrin domain-containing protein 3
- p38
p38 mitogen-activated protein kinase
- PI3K
phosphatidylinositol 3-kinase
- PTM(s)
post-translational modification(s)
- RAGE
receptor for advanced glycation end-products
- ROS
reactive oxygen species; sRAGE, soluble receptor for advanced glycation end-products
- SA-AKI
sepsis-associated acute kidney injury
- S100A8/A9
heterodimer of S100A8 and S100A9
- siRNA
small interfering RNA
- SOP(s)
standard operating procedure(s)
- TLR4
toll-like receptor 4
- TNF-α
tumor necrosis factor alpha
- VCAM-1
vascular cell adhesion molecule-1
- [TIMP-2]·[IGFBP7]
(tissue inhibitor of metalloproteinases-2 × insulin-like growth factor-binding protein 7).
References
1
AgrawalL.EngelK. B.GreytakS. R.MooreH. M. (2018). Understanding preanalytical variables and their effects on clinical biomarkers of oncology and immunotherapy. Semin. Cancer Biol.52, 26–38. 10.1016/j.semcancer.2017.12.008
2
AguilarM. G.AlHussenH. A.GandhiP. D.KaurP.PothacamuriM. A.TalikotiM. A. H.et al (2024). Sepsis-associated acute kidney injury: pathophysiology and treatment modalities. Cureus16, e75992. 10.7759/cureus.75992
3
AndreassonU.Perret-LiaudetA.Van Waalwijk Van DoornL. J. C.BlennowK.ChiasseriniD.EngelborghsS.et al (2015). A practical guide to immunoassay method validation. Front. Neurol.6, 179. 10.3389/fneur.2015.00179
4
ArendshorstW. J.VendrovA. E.KumarN.GaneshS. K.MadamanchiN. R. (2024). Oxidative stress in kidney injury and hypertension. Antioxidants13, 1454. 10.3390/antiox13121454
5
BaesemanL.GunningS.KoynerJ. L. (2024). Biomarker enrichment in sepsis-associated acute kidney injury: finding high-risk patients in the intensive care unit. Am. J. Nephrol.55, 72–85. 10.1159/000534608
6
BagheriV. (2022). S100A12 is not expressed in rodents: transgenic mouse model is needed. Mol. Immunol.152, 35. 10.1016/j.molimm.2022.10.003
7
BerthelootD.LatzE. (2017). HMGB1, IL-1α, IL-33 and S100 proteins: dual-function alarmins. Cell. Mol. Immunol.14, 43–64. 10.1038/cmi.2016.34
8
BrozatJ. F.HarbalioğluN.HohlsteinP.Abu JhaishaS.PollmannsM. R.AdamsJ. K.et al (2024). Elevated serum KIM-1 in sepsis correlates with kidney dysfunction and the severity of multi-organ critical illness. Int. J. Mol. Sci.25, 5819. 10.3390/ijms25115819
9
CaoR.-N.TangL.XiaZ.-Y.XiaR. (2019). Endothelial glycocalyx as a potential therapeutic target in organ injuries. Chin. Med. J. (Engl.)132, 963–975. 10.1097/CM9.0000000000000177
10
CarvalhoA.LuJ.FrancisJ. D.MooreR. E.HaleyK. P.DosterR. S.et al (2020). S100A12 in digestive diseases and health: a scoping review. Gastroenterol. Res. Pract.2020, 1–11. 10.1155/2020/2868373
11
ChuW.SunX.YanY. (2025). Study on the regulation of renal tubular cell apoptosis by SIRT1/NF-κB signaling pathway in septic acute kidney injury. Ren. Fail.47, 2499904. 10.1080/0886022X.2025.2499904
12
CicchinelliS.PignataroG.GemmaS.PiccioniA.PicozziD.OjettiV.et al (2024). PAMPs and DAMPs in sepsis: a review of their molecular features and potential clinical implications. Int. J. Mol. Sci.25, 962–1002. 10.3390/ijms25020962
13
CrossK.VetterS. W.AlamY.HasanMd. Z.NathA. D.LeclercE. (2024). Role of the receptor for advanced glycation end products (RAGE) and its ligands in inflammatory responses. Biomolecules14, 1550. 10.3390/biom14121550
14
CundenL. S.GaillardA.NolanE. M. (2016). Calcium ions tune the zinc-sequestering properties and antimicrobial activity of human S100A12. Chem. Sci.7, 1338–1348. 10.1039/C5SC03655K
15
CurranC. S.KoppJ. B. (2022). RAGE pathway activation and function in chronic kidney disease and COVID-19. Front. Med.9, 970423. 10.3389/fmed.2022.970423
16
DaffuG.Del PozoC.O’SheaK.AnanthakrishnanR.RamasamyR.SchmidtA. (2013). Radical roles for RAGE in the pathogenesis of oxidative stress in cardiovascular diseases and beyond. Int. J. Mol. Sci.14, 19891–19910. 10.3390/ijms141019891
17
DongH.ZhangY.HuangY.DengH. (2022). Pathophysiology of RAGE in inflammatory diseases. Front. Immunol.13, 931473. 10.3389/fimmu.2022.931473
18
DuboisC.MarcéD.FaivreV.LukaszewiczA. C.JunotC.FenailleF.et al (2019). High plasma level of S100A8/S100A9 and S100A12 at admission indicates a higher risk of death in septic shock patients. Sci. Rep.9, 15752. 10.1038/s41598-019-52184-8
19
EwaishaR.AndersonK. S. (2023). Immunogenicity of CRISPR therapeutics—critical considerations for clinical translation. Front. Bioeng. Biotechnol.11, 1138596. 10.3389/fbioe.2023.1138596
20
FoellD.WittkowskiH.VoglT.RothJ. (2007). S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J. Leukoc. Biol.81, 28–37. 10.1189/jlb.0306170
21
FoellD.WittkowskiH.KesselC.LükenA.WeinhageT.VargaG.et al (2013). Proinflammatory S100A12 can activate human monocytes via toll-like receptor 4. Am. J. Respir. Crit. Care Med.187, 1324–1334. 10.1164/rccm.201209-1602OC
22
GawdzikJ.MathewL.KimG.PuriT. S.Hofmann BowmanM. A. (2011). Vascular remodeling and arterial calcification are directly mediated by S100A12 (EN-RAGE) in chronic kidney disease. Am. J. Nephrol.33, 250–259. 10.1159/000324693
23
GomezH.InceC.De BackerD.PickkersP.PayenD.HotchkissJ.et al (2014). A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock41, 3–11. 10.1097/SHK.0000000000000052
24
GoyetteJ.GeczyC. L. (2011). Inflammation-associated S100 proteins: new mechanisms that regulate function. Amino Acids41, 821–842. 10.1007/s00726-010-0528-0
25
GustotT. (2011). Multiple organ failure in sepsis: prognosis and role of systemic inflammatory response. Curr. Opin. Crit. Care17, 153–159. 10.1097/MCC.0b013e328344b446
26
HaririG.LegrandM. (2025). New drugs for acute kidney injury. J. Intensive Med.5, 3–11. 10.1016/j.jointm.2024.08.001
27
HatoT.DagherP. C. (2025). Molecular mechanisms of sepsis-associated acute kidney injury. J. Am. Soc. Nephrol.36, 2259–2268. 10.1681/ASN.0000000809
28
HaydingerC. D.AshanderL. M.TanA. C. R.SmithJ. R. (2023). Intercellular adhesion molecule 1: more than a leukocyte adhesion molecule. Biology12, 743. 10.3390/biology12050743
29
HeR.-R.YueG.-L.DongM.-L.WangJ.-Q.ChengC. (2024). Sepsis biomarkers: advancements and clinical applications—a narrative review. Int. J. Mol. Sci.25, 9010. 10.3390/ijms25169010
30
Hofmann BowmanM.WilkJ.HeydemannA.KimG.RehmanJ.LodatoJ. A.et al (2010). S100A12 mediates aortic wall remodeling and aortic aneurysm. Circ. Res.106, 145–154. 10.1161/CIRCRESAHA.109.209486
31
Hofmann BowmanM. A.HeydemannA.GawdzikJ.ShillingR. A.Camoretti‐MercadoB. (2011). Transgenic expression of human S100A12 induces structural airway abnormalities and limited lung inflammation in a mouse model of allergic inflammation. Clin. Exp. Allergy41, 878–889. 10.1111/j.1365-2222.2011.03714.x
32
HuangX.YuZ.ZhuoZ. (2025). S100A12 as a key biomarker in a neutrophil-associated gene prediction model for sepsis diagnosis. Med. Baltim.104, e46140. 10.1097/MD.0000000000046140
33
IslamuddinM.QinX. (2024). Renal macrophages and NLRP3 inflammasomes in kidney diseases and therapeutics. Cell Death Discov.10, 229. 10.1038/s41420-024-01996-3
34
JungJ.-Y.KimJ.-W.SuhC.-H.KimH.-A. (2020). Roles of interactions between toll-like receptors and their endogenous ligands in the pathogenesis of systemic juvenile idiopathic arthritis and adult-onset still’s disease. Front. Immunol.11, 583513. 10.3389/fimmu.2020.583513
35
KangH.-Y.ParkS. Y.KimG.NamB. Y.ParkJ. T.KimD. K.et al (2025). Soluble receptor for advanced glycation end products attenuates sepsis-associated acute kidney injury. Kidney Res. Clin. Pract.44, 1–15. 10.23876/j.krcp.25.072
36
KimC. H.KangH.-Y.KimG.ParkJ.NamB. Y.ParkJ. T.et al (2023). Soluble receptors for advanced glycation end-products prevent unilateral ureteral obstruction-induced renal fibrosis. Front. Pharmacol.14, 1172269. 10.3389/fphar.2023.1172269
37
KimH.-J.KimH.LeeJ.-H.HwangboC. (2023). Toll-like receptor 4 (TLR4): new insight immune and aging. Immun. Ageing20, 67. 10.1186/s12979-023-00383-3
38
KodiT.SankheR.GopinathanA.NandakumarK.KishoreA. (2024). New insights on NLRP3 inflammasome: mechanisms of activation, inhibition, and epigenetic regulation. J. Neuroimmune Pharmacol.19, 7. 10.1007/s11481-024-10101-5
39
KongD.-H.KimY.KimM.JangJ.LeeS. (2018). Emerging roles of vascular cell adhesion molecule-1 (VCAM-1) in immunological disorders and cancer. Int. J. Mol. Sci.19, 1057. 10.3390/ijms19041057
40
KounatidisD.TzivakiI.DaskalopoulouS.DaskouA.AdamouA.RigatouA.et al (2024). Sepsis-associated acute kidney injury: what’s new regarding its diagnostics and therapeutics?Diagnostics14, 2845. 10.3390/diagnostics14242845
41
KuwabaraS.GogginsE.OkusaM. D. (2022). The pathophysiology of sepsis-associated AKI. Clin. J. Am. Soc. Nephrol.17, 1050–1069. 10.2215/CJN.00850122
42
LakeB. B.MenonR.WinfreeS.HuQ.Melo FerreiraR.KalhorK.et al (2023). An atlas of healthy and injured cell states and niches in the human kidney. Nature619, 585–594. 10.1038/s41586-023-05769-3
43
LegrandM.BagshawS. M.BhatrajuP. K.BihoracA.CanigliaE.KhannaA. K.et al (2024). Sepsis-associated acute kidney injury: recent advances in enrichment strategies, sub-phenotyping and clinical trials. Crit. Care28, 92. 10.1186/s13054-024-04877-4
44
Lenga Ma BondaW.FournetM.ZhaiR.LutzJ.BlondonnetR.BourgneC.et al (2022). Receptor for advanced glycation end-products promotes activation of alveolar macrophages through the NLRP3 inflammasome/TXNIP axis in acute lung injury. Int. J. Mol. Sci.23, 11659. 10.3390/ijms231911659
45
LiX.TangJ.XuJ.ZhuM.CaoJ.LiuY.et al (2014). The inflammation-related gene S100A12 is positively regulated by C/EBPβ and AP-1 in pigs. Int. J. Mol. Sci.15, 13802–13816. 10.3390/ijms150813802
46
LiY.HeY.ChenS.WangQ.YangY.ShenD.et al (2022). S100A12 as biomarker of disease severity and prognosis in patients with idiopathic pulmonary fibrosis. Front. Immunol.13, 810338. 10.3389/fimmu.2022.810338
47
LiS.LivingstonM. J.MaZ.HuX.WenL.DingH.-F.et al (2023). Tubular cell senescence promotes maladaptive kidney repair and chronic kidney disease after cisplatin nephrotoxicity. JCI Insight8, e166643. 10.1172/jci.insight.166643
48
LiliensiekB.WeigandM. A.BierhausA.NicklasW.KasperM.HoferS.et al (2004). Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response. J. Clin. Invest.113, 1641–1650. 10.1172/JCI200418704
49
LinH.XiongW.FuL.YiJ.YangJ. (2025). Damage-associated molecular patterns (DAMPs) in diseases: implications for therapy. Mol. Biomed.6, 60. 10.1186/s43556-025-00305-3
50
LinS.YanJ.HeS.LuoL. (2025). Identification of pyroptosis-related gene S100A12 as a potential diagnostic biomarker for sepsis through bioinformatics analysis and machine learning. Mol. Immunol.183, 44–55. 10.1016/j.molimm.2025.04.009
51
Lira-JuniorR.HolmströmS. B.ClarkR.ZwickerS.MajsterM.JohannsenG.et al (2020). S100A12 expression is modulated during monocyte differentiation and reflects periodontitis severity. Front. Immunol.11, 86. 10.3389/fimmu.2020.00086
52
LiuY.KongX.YouY.XiangL.ZhangY.WuR.et al (2022). S100A8-mediated NLRP3 inflammasome-dependent pyroptosis in macrophages facilitates liver fibrosis progression. Cells11, 3579. 10.3390/cells11223579
53
LiuY.PanR.OuyangY.GuW.XiaoT.YangH.et al (2024). Pyroptosis in health and disease: mechanisms, regulation and clinical perspective. Signal Transduct. Target. Ther.9, 245. 10.1038/s41392-024-01958-2
54
LlitjosJ.-F.CarrolE. D.OsuchowskiM. F.BonnevilleM.SciclunaB. P.PayenD.et al (2024). Enhancing sepsis biomarker development: key considerations from public and private perspectives. Crit. Care28, 238. 10.1186/s13054-024-05032-9
55
LudesP.-O.De RoquetailladeC.ChoustermanB. G.PottecherJ.MebazaaA. (2021). Role of damage-associated molecular patterns in septic acute kidney injury, from injury to recovery. Front. Immunol.12, 606622. 10.3389/fimmu.2021.606622
56
McMullanR. R.McAuleyD. F.O’KaneC. M.SilversidesJ. A. (2024). Vascular leak in sepsis: physiological basis and potential therapeutic advances. Crit. Care28, 97. 10.1186/s13054-024-04875-6
57
MeijerB.GearryR. B.DayA. S. (2012). The role of S100A12 as a systemic marker of inflammation. Int. J. Inflamm.2012, 1–6. 10.1155/2012/907078
58
MorozO. V.AntsonA. A.MurshudovG. N.MaitlandN. J.DodsonG. G.WilsonK. S.et al (2001). The three-dimensional structure of human S100A12. Acta Crystallogr. D. Biol. Crystallogr.57, 20–29. 10.1107/S090744490001458X
59
MorozO. V.DodsonG. G.WilsonK. S.LukanidinE.BronsteinI. B. (2003). Multiple structural states of S100A12: a key to its functional diversity. Microsc. Res. Tech.60, 581–592. 10.1002/jemt.10300
60
MorozO. V.BurkittW.WittkowskiH.HeW.IanoulA.NovitskayaV.et al (2009). Both Ca2+ and Zn2+ are essential for S100A12 protein oligomerization and function. BMC Biochem.10, 11. 10.1186/1471-2091-10-11
61
MotomuraK.RomeroR.PlazyoO.Garcia-FloresV.GershaterM.GalazJ.et al (2021). The alarmin S100A12 causes sterile inflammation of the human chorioamniotic membranes as well as preterm birth and neonatal mortality in mice. Biol. Reprod.105, 1494–1509. 10.1093/biolre/ioab188
62
NgT. K. S.Udeh‐MomohC.LimM.GleerupH. S.LeifertW.AjaloC.et al (2025). Guidelines for the standardization of pre‐analytical variables for salivary biomarker studies in Alzheimer’s disease research: an updated review and consensus of the salivary biomarkers for dementia research working group. Alzheimer’s Dement.21, e14420. 10.1002/alz.14420
63
NiuX.WangC.LiH.ChenW. (2024). Role of OPG/RANKL/RANK/TLR4 signaling pathway in sepsis-associated acute kidney injury. BMC Nephrol.25, 205. 10.1186/s12882-024-03648-1
64
OesterleA.Hofmann BowmanM. A. (2015). S100A12 and the S100/calgranulins: emerging biomarkers for atherosclerosis and possibly therapeutic targets. Arterioscler. Thromb. Vasc. Biol.35, 2496–2507. 10.1161/ATVBAHA.115.302072
65
Ortín-BustilloA.BotíaM.López-MartínezM. J.Martínez-SubielaS.CerónJ. J.González-BulnesA.et al (2023). Changes in S100A8/A9 and S100A12 and their comparison with other analytes in the saliva of pigs with diarrhea due to E. coli. Animals13, 2556. 10.3390/ani13162556
66
OstermannM.LegrandM.MeerschM.SrisawatN.ZarbockA.KellumJ. A. (2024). Biomarkers in acute kidney injury. Ann. Intensive Care14, 145. 10.1186/s13613-024-01360-9
67
OttL. W.ResingK. A.SizemoreA. W.HeyenJ. W.CocklinR. R.PedrickN. M.et al (2007). Tumor necrosis factor-α- and interleukin-1-induced cellular responses: coupling proteomic and genomic information. J. Proteome Res.6, 2176–2185. 10.1021/pr060665l
68
O’BryantS. E.GuptaV.HenriksenK.EdwardsM.JerominA.ListaS.et al (2015). Guidelines for the standardization of preanalytic variables for blood‐based biomarker studies in alzheimer’s disease research. Alzheimer’s Dement.11, 549–560. 10.1016/j.jalz.2014.08.099
69
PietzschJ.HoppmannS. (2009). Human S100A12: a novel key player in inflammation?Amino Acids36, 381–389. 10.1007/s00726-008-0097-7
70
QinS.BieF.ChenS.XuY.ChenL.ShuB.et al (2024). Targeting S100A12 to improve angiogenesis and accelerate diabetic wound healing. Inflammation48, 633–648. 10.1007/s10753-024-02073-8
71
RaiV.MathewsG.K AgrawalD. (2022). Translational and clinical significance of DAMPs, PAMPs, and PRRs in trauma-induced inflammation. Arch. Clin. Biomed. Res.6, 1–20. 10.26502/acbr.50170279
72
RashidH.JaliA.AkhterM. S.AbdiS. A. H. (2023). Molecular mechanisms of oxidative stress in acute kidney injury: targeting the loci by resveratrol. Int. J. Mol. Sci.25, 3. 10.3390/ijms25010003
73
RazE. (2007). Organ-specific regulation of innate immunity. Nat. Immunol.8, 3–4. 10.1038/ni0107-3
74
RojasA.LindnerC.SchneiderI.GonzalezI.UribarriJ. (2024). The RAGE axis: a relevant inflammatory hub in human diseases. Biomolecules14, 412. 10.3390/biom14040412
75
RouleauP.VandalK.RyckmanC.PoubelleP. E.BoivinA.TalbotM.et al (2003). The calcium-binding protein S100A12 induces neutrophil adhesion, migration, and release from bone marrow in mouse at concentrations similar to those found in human inflammatory arthritis. Clin. Immunol.107, 46–54. 10.1016/S1521-6616(02)00043-8
76
RussoA. J.VasudevanS. O.Méndez-HuergoS. P.KumariP.MenoretA.DuduskarS.et al (2021). Intracellular immune sensing promotes inflammation via gasdermin D–driven release of a lectin alarmin. Nat. Immunol.22, 154–165. 10.1038/s41590-020-00844-7
77
SeibertF. S.SitzM.PassfallJ.HaesnerM.LaschinskiP.BuhlM.et al (2021). Urinary calprotectin, NGAL, and KIM-1 in the differentiation of primarily inflammatory vs. non-inflammatory stable chronic kidney diseases. Ren. Fail.43, 417–424. 10.1080/0886022X.2021.1885442
78
ShenC.MaY.ZengZ.YinQ.HongY.HouX.et al (2017). RAGE-specific inhibitor FPS-ZM1 attenuates AGEs-induced neuroinflammation and oxidative stress in rat primary microglia. Neurochem. Res.42, 2902–2911. 10.1007/s11064-017-2321-x
79
SinghP.AliS. A. (2022). Multifunctional role of S100 protein family in the immune system: an update. Cells11, 2274. 10.3390/cells11152274
80
SuL.ZhangJ.GomezH.KellumJ. A.PengZ. (2023). Mitochondria ROS and mitophagy in acute kidney injury. Autophagy19, 401–414. 10.1080/15548627.2022.2084862
81
SuttonT. A. (2009). Alteration of microvascular permeability in acute kidney injury. Microvasc. Res.77, 4–7. 10.1016/j.mvr.2008.09.004
82
TanakaN.IkariJ.AnazawaR.SuzukiM.KatsumataY.ShimadaA.et al (2019). S100A12 inhibits fibroblast migration via the receptor for advanced glycation end products and p38 MAPK signaling. Vitro Cell. Dev. Biol. Anim.55, 656–664. 10.1007/s11626-019-00384-x
83
VallésP. G.Gil LorenzoA. F.GarciaR. D.CacciamaniV.BenardonM. E.CostantinoV. V. (2023). Toll-like receptor 4 in acute kidney injury. Int. J. Mol. Sci.24, 1415. 10.3390/ijms24021415
84
WangK.XieS.XiaoK.YanP.HeW.XieL. (2018). Biomarkers of sepsis-induced acute kidney injury. Biomed. Res. Int.2018, 1–7. 10.1155/2018/6937947
85
WangQ.AleshintsevA.BoltonD.ZhuangJ.BrenowitzM.GuptaR. (2019). Ca(II) and Zn(II) cooperate to modulate the structure and self-assembly of S100A12. Biochemistry58, 2269–2281. 10.1021/acs.biochem.9b00123
86
WangH.JiX.WangA. Y.WuP. K.LiuZ.DongL.et al (2021). Epidemiology of sepsis-associated acute kidney injury in Beijing, China: a descriptive analysis. Int. J. Gen. Med.14, 5631–5649. 10.2147/IJGM.S320768
87
WangT.HuangY.ZhangX.ZhangY.ZhangX. (2024). Advances in metabolic reprogramming of renal tubular epithelial cells in sepsis-associated acute kidney injury. Front. Physiol.15, 1329644. 10.3389/fphys.2024.1329644
88
WangX.LuoY.ZhouQ.MaJ. (2025). The roles of S100A8/A9 and S100A12 in autoimmune diseases: mechanisms, biomarkers, and therapeutic potential. Autoimmun. Rev.24, 103920. 10.1016/j.autrev.2025.103920
89
WuH.-P.ChuangL.-P.LiuP.-H.ChuC.-M.YuC.-C.LinS.-W.et al (2022). Decreased monocyte HLA-DR expression in patients with sepsis and acute kidney injury. Medicina58, 1198. 10.3390/medicina58091198
90
WuF.HongH.TianY.WangX. (2025). Serum S100A12 in the clinical diagnosis of sepsis-induced myocardial dysfunction: an integrated bioinformatics and clinical data analysis. Front. Cardiovasc. Med.12, 1640788. 10.3389/fcvm.2025.1640788
91
WuW.LanW.JiaoX.WangK.DengY.ChenR.et al (2025). Pyroptosis in sepsis-associated acute kidney injury: mechanisms and therapeutic perspectives. Crit. Care29, 168. 10.1186/s13054-025-05329-3
92
XiaP.JiX.YanL.LianS.ChenZ.LuoY. (2023). Roles of S100A8, S100A9 and S100A12 in infection, inflammation and immunity. Immunology169, 198–210. 10.1111/imm.13722
93
XiaY.GuanY.LiangJ.WuW. (2024). TAK-242 improves sepsis-associated acute kidney injury in rats by inhibiting the TLR4/NF-κB signaling pathway. Ren. Fail.46, 2313176. 10.1080/0886022X.2024.2313176
94
XieJ.MéndezJ. D.Méndez-ValenzuelaV.Aguilar-HernándezM. M. (2013). Cellular signalling of the receptor for advanced glycation end products (RAGE). Cell. Signal.25, 2185–2197. 10.1016/j.cellsig.2013.06.013
95
XieY.HuangP.ZhangJ.TianR.JinW.XieH.et al (2021). Biomarkers for the diagnosis of sepsis-associated acute kidney injury: systematic review and meta-analysis. Ann. Palliat. Med.10, 4159–4173. 10.21037/apm-20-1855
96
XuL.GuoJ.MoledinaD. G.CantleyL. G. (2022). Immune-mediated tubule atrophy promotes acute kidney injury to chronic kidney disease transition. Nat. Commun.13, 4892. 10.1038/s41467-022-32634-0
97
YanW. X.ArmishawC.GoyetteJ.YangZ.CaiH.AlewoodP.et al (2008). Mast cell and monocyte recruitment by S100A12 and its Hinge domain. J. Biol. Chem.283, 13035–13043. 10.1074/jbc.M710388200
98
YanL.BjorkP.ButucR.GawdzikJ.EarleyJ.KimG.et al (2013). Beneficial effects of quinoline-3-carboxamide (ABR-215757) on atherosclerotic plaque morphology in S100A12 transgenic ApoE null mice. Atherosclerosis228, 69–79. 10.1016/j.atherosclerosis.2013.02.023
99
YangZ.TaoT.RafteryM. J.YoussefP.Di GirolamoN.GeczyC. L. (2001). Proinflammatory properties of the human S100 protein S100A12. J. Leukoc. Biol.69, 986–994. 10.1189/jlb.69.6.986
100
YangZ.YanW. X.CaiH.TedlaN.ArmishawC.Di GirolamoN.et al (2007). S100A12 provokes mast cell activation: a potential amplification pathway in asthma and innate immunity. J. Allergy Clin. Immunol.119, 106–114. 10.1016/j.jaci.2006.08.021
101
YangH.FengL.JiangZ.WuX.ZengK. (2024). Amlexanox reduces new-onset atrial fibrillation risk in sepsis by downregulating S100A12: a Mendelian randomization study. Front. Cardiovasc. Med.11, 1401314. 10.3389/fcvm.2024.1401314
102
YangH.ChenY.HeJ.LiY.FengY. (2025). Advances in the diagnosis of early biomarkers for acute kidney injury: a literature review. BMC Nephrol.26, 115. 10.1186/s12882-025-04040-3
103
ZarbockA.KoynerJ. L.GomezH.PickkersP.ForniL.Acute Disease Quality Initiative group (2023a). Sepsis-associated acute kidney injury—treatment standard. Nephrol. Dial. Transpl.39, 26–35. 10.1093/ndt/gfad142
104
ZarbockA.NadimM. K.PickkersP.GomezH.BellS.JoannidisM.et al (2023b). Sepsis-associated acute kidney injury: consensus report of the 28th acute disease quality initiative workgroup. Nat. Rev. Nephrol.19, 401–417. 10.1038/s41581-023-00683-3
105
ZhangW. (2024). Critical roles of S100A12, MMP9, and PRTN3 in sepsis diagnosis: insights from multiple microarray data analyses. Comput. Biol. Med.171, 108222. 10.1016/j.compbiomed.2024.108222
106
ZhangC.-F.WangH.-J.TongZ.-H.ZhangC.WangY.-S.YangH.-Q.et al (2020). The diagnostic and prognostic values of serum and urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in sepsis induced acute renal injury patients. Eur. Rev. Med. Pharmacol. Sci.24, 5604–5617. 10.26355/eurrev_202005_21346
107
ZhangZ.HanN.ShenY. (2020). S100A12 promotes inflammation and cell apoptosis in sepsis-induced ARDS via activation of NLRP3 inflammasome signaling. Mol. Immunol.122, 38–48. 10.1016/j.molimm.2020.03.022
108
ZhangX.AgborbesongE.LiX. (2021). The role of mitochondria in acute kidney injury and chronic kidney disease and its therapeutic potential. Int. J. Mol. Sci.22, 11253. 10.3390/ijms222011253
109
ZhangH.DengZ.WangY.ZhengX.ZhouL.YanS.et al (2023). CHIP protects against septic acute kidney injury by inhibiting NLRP3-mediated pyroptosis. IScience26, 107762. 10.1016/j.isci.2023.107762
110
ZhangW.JiangL.TongX.HeH.ZhengY.XiaZ. (2024). Sepsis-induced endothelial dysfunction: permeability and regulated cell death. J. Inflamm. Res.17, 9953–9973. 10.2147/JIR.S479926
111
ZhaoL.HaoY.TangS.HanX.LiR.ZhouX. (2023). Energy metabolic reprogramming regulates programmed cell death of renal tubular epithelial cells and might serve as a new therapeutic target for acute kidney injury. Front. Cell Dev. Biol.11, 1276217. 10.3389/fcell.2023.1276217
112
ZhaoS.LiaoJ.ShenM.LiX.WuM. (2023). Epigenetic dysregulation of autophagy in sepsis-induced acute kidney injury: the underlying mechanisms for renoprotection. Front. Immunol.14, 1180866. 10.3389/fimmu.2023.1180866
113
ZhouY.ZhaY.YangY.MaT.LiH.LiangJ. (2023). S100 proteins in cardiovascular diseases. Mol. Med.29, 68. 10.1186/s10020-023-00662-1
114
ZhuY.XuD.DengF.YanY.LiJ.ZhangC.et al (2021). Angiotensin (1-7) attenuates sepsis-induced acute kidney injury by regulating the NF-κB pathway. Front. Pharmacol.12, 601909. 10.3389/fphar.2021.601909
Summary
Keywords
biomarker, inflammation, metabolic reprogramming, RAGE, S100A12, sepsis, sepsis-associated acute kidney injury, TLR4
Citation
Liu H, Lv Y, Xue Q and Shi J (2026) S100A12 drives inflammatory and metabolic reprogramming in sepsis-associated acute kidney injury. Front. Mol. Biosci. 13:1741799. doi: 10.3389/fmolb.2026.1741799
Received
07 November 2025
Revised
11 January 2026
Accepted
12 January 2026
Published
23 January 2026
Volume
13 - 2026
Edited by
Giosiana Bosco, University of Catania, Italy
Reviewed by
Lakshminarayan Reddy Teegala, University of Toledo Medical Center, United States
Maurizio Di Marco, University of Catania, Italy
Updates
Copyright
© 2026 Liu, Lv, Xue and Shi.
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*Correspondence: Jikui Shi, sjkjnrmyy@126.com
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