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.

S100A12 orchestrates multiple aspects of the inflammatory cascade in SA-AKI through interconnected mechanisms.

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).

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.

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).

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.

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.

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).

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).

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.

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.

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.

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.

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).

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).

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).

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.