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Review

Pancreatic Stone Protein: A Multifaceted Biomarker—A Comprehensive Review

by
Nika Vlahović Vlašić
1,2,*,
Lada Zibar
3,4,
Petra Smajić
1,2,
Luka Švitek
1,2 and
Domagoj Drenjančević
1,5
1
Clinic for Infectious Diseases, University Hospital Centre Osijek, 31000 Osijek, Croatia
2
Department of Infectology and Dermatovenerology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
3
Clinic for Internal Medicine, Clinical Hospital Merkur, 10000 Zagreb, Croatia
4
Department of Pathophysiology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
5
Department of Microbiology and Parasitology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
*
Author to whom correspondence should be addressed.
Acta Microbiol. Hell. 2025, 70(3), 35; https://doi.org/10.3390/amh70030035
Submission received: 16 July 2025 / Revised: 28 August 2025 / Accepted: 4 September 2025 / Published: 9 September 2025
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Abstract

Background: Pancreatic stone protein (PSP) has emerged as a promising biomarker for the early diagnosis of sepsis, infectious diseases, and chronic inflammatory conditions, including cancer, diabetes, and inflammatory bowel disease. This review evaluates the role of PSP as a biomarker and functional protein, emphasizing its diagnostic and prognostic value. Methods: This review was conducted through a comprehensive literature search using the PubMed database, covering publications from the discovery of PSP in the 1980s up to 2025. The information was gathered into thematic sections to provide a comprehensive and structured review of PSP as a biomarker and functional protein in health and disease. Results: A total of 256 articles were reviewed and critically assessed, with 80 meeting the inclusion criteria and forming the basis of this review. The reviewed literature underscores PSP as a multifaceted protein involved in inflammation, immune modulation, tissue regeneration, and systemic infection. PSP shows promise as an early biomarker in critically ill patients. Conclusions: PSP is a clinically promising but not yet fully validated biomarker. To enable its routine clinical application, standardized diagnostic cutoffs, validation through multicenter trials, and integration with existing biomarker panels are required. Further research is warranted to fully establish its diagnostic and prognostic potential across diverse clinical settings.

1. Introduction

Pancreatic stone protein (PSP) has been studied for over four decades, yet its full clinical significance remains incompletely understood. Initially identified for its potential role in inhibiting pancreatic stone formation [1], PSP has since been implicated in diverse physiological and pathological processes, including tissue regeneration, beta cell maintenance, immune modulation, antimicrobial defense, and cellular stress responses [2,3,4]. Recent studies have highlighted PSP’s potential as a biomarker for sepsis and systemic inflammation, demonstrating early rises in PSP levels during systemic inflammatory responses and suggesting its utility in risk stratification [5]. However, the existing literature is fragmented, with findings often limited to specific disease contexts or small cohorts. Conflicting evidence regarding PSP’s specificity, diagnostic accuracy, and prognostic value in various conditions, including infections, malignancies, renal dysfunction, and neurodegenerative diseases, underscores the need for a comprehensive synthesis. Despite increasing interest, no standardized diagnostic thresholds or clinical guidelines for PSP currently exist. Moreover, its role relative to established biomarkers, such as procalcitonin (PCT) and C-reactive protein (CRP), remains unclear.
This review aims to consolidate the current knowledge on PSP by critically evaluating its molecular characteristics, biological functions, and clinical applications across a range of diseases. By identifying key limitations and proposing future directions, this review aims to guide clinicians and researchers in the application of PSP as a diagnostic and prognostic marker in diverse clinical settings.

2. Materials and Methods

This review was conducted through a comprehensive search of the PubMed database, using the terms pancreatic stone protein or PSP or lithostathine or pancreatic thread protein and sepsis or infection or inflammation or biomarker. Filters included English-language publications up to 2025. Boolean operators ensured comprehensive coverage of synonyms and clinical contexts. Additional references were identified through citation tracking. To determine eligibility for synthesis, we screened titles and abstracts, then assessed full texts to ensure relevance to our predefined outcome domains, such as PSP’s role in infection, inflammation, sepsis diagnosis, etc.
This review included studies that reported original research, clinical studies, experimental studies, or substantial reviews related to the molecular characteristics, biological functions, or clinical applications of PSP. Specifically, articles focusing on PSP’s role in pancreatic health, tissue regeneration, immune modulation, antimicrobial defense, inflammation, beta cell function, diabetes, cancer, renal dysfunction, neurodegenerative diseases, and sepsis were included. Studies were excluded if they were not published in English, lacked original data or substantive analysis of PSP (such as conference abstracts without full texts), or focused exclusively on unrelated proteins or biomarkers. Additionally, studies that mentioned PSP in passing without presenting relevant findings were also excluded.
Studies were subgrouped into specific thematic categories based on clinical context. To explore heterogeneity, we conducted subgroup analyses by clinical setting, population, and measurement technique. Sensitivity analyses were carried out by excluding high-risk or methodologically limited studies to test the robustness of our conclusions. When multiple studies addressed the same topic, we prioritized the inclusion of the article with the most comprehensive methodology and detailed reporting. For synthesis, we used a narrative approach due to variability in study design and outcomes.
All five authors independently collected data, ensuring methodological consistency and accuracy, with each author serving as an individual reviewer throughout the data extraction process. The data were sought on all predefined outcome domains, including biomarker levels, diagnostic accuracy, clinical relevance, and prognostic value of pancreatic stone protein, and we extracted all results compatible with these outcomes across studies—regardless of measurement methods, time points, or analysis types—to ensure comprehensive and unbiased inclusion.

3. Results

A total of 256 articles were reviewed and critically assessed, of which 80 met the inclusion criteria and were included in this review. During the selection process, one study was excluded for not being published in English, fifty-four reports were excluded for focusing primarily on other biomarkers, and three reports were excluded due to a lack of relevant findings related to pancreatic stone protein. This selection process is summarized in the PRISMA 2020 flow diagram (Figure 1).
The findings were synthesized thematically to provide a comprehensive and cohesive overview of PSP’s evolving roles in health and disease. The evidence highlights PSP’s progression from a proposed inhibitor of pancreatic stone formation to a multifaceted biomarker involved in tissue regeneration, immune modulation, and systemic inflammation.

4. Discussion

4.1. Pancreatic Stone Protein: Evolution of Nomenclature, Function, and Its Role in Pancreatic Health

Pancreatic stone protein is a protein that in the 1980s captured significant interest for its potential role in regulating crystal growth and preventing stone formation in the pancreas. Initially discovered and named pancreatic thread protein (PTP) due to its filamentous appearance in solutions, PSP was later associated with calcium-binding activity, leading to its identification as a potential inhibitor of pancreatic stones [6]. Remarkably, two independent research groups isolated this protein around the same time, designating it as either “pancreatic stone protein”, later also lithostatine, or “pancreatic thread protein,” highlighting the ongoing evolution of its nomenclature [1].
PSP has been found not only in the pancreatic secretions of patients with pancreatic disorders but also in healthy individuals, suggesting its broader physiological role in pancreatic function. Interestingly, while early studies suggested reduced PSP levels in chronic pancreatitis patients, later research using varying immunoassays yielded mixed results [7]. Further investigation by Bimmler et al. and subsequent studies questioned PSP’s role in calcium carbonate crystal inhibition, raising doubts about its effectiveness in stone prevention and prompting a re-evaluation of the name “lithostathine” [8].
Additionally, PSP was found to be uniformly present in pancreatic and duodenal extracts, initially not detected in other tissues, underscoring its unique association with pancreas [9].
The Reg 1 gene (regenerating gene one) is part of a protein family that includes Reg 1, 3, and 4. These proteins are present in various organ systems, such as the digestive and nervous system. Reg 1 is molecularly identical to PSP, representing the same polypeptide product encoded by the same gene. Reg 1α (Regenerating gene 1 alpha), a human variant of the Reg 1 protein, is composed of two domains (C-type lectin and N-terminal peptide) [10]. The dual naming reflects its discovery in different contexts—first for its role in pancreatic health and later for its broader regenerative functions.

4.2. Serum PSP Levels: Variations in Health, Disease, and Across the Lifespan

Serum PSP levels have been widely studied to explore their changes in health and disease. PSP is initially secreted by acinar cells in the duodenum as a 16 kDa glycoprotein, which is then broken down by trypsin into a 14 kDa form in pancreatic juice. The 14 kDa PSP is insoluble and not reabsorbed into the bloodstream. Therefore, serum PSP levels reflect the concentration of the 16 kDa form [5]. In 1993, a study examined PSP levels in control individuals and patients with various conditions. In healthy controls, the serum PSP ranged from 25.2 to 161.1 ng/mL, with a mean of 78.6 ng/mL and a 95% range (mean ± 2 SD) of 15–142.2 ng/mL. Concentrations above 142.2 ng/mL were classified as abnormally high, while those below 15 ng/mL were abnormally low. The study found elevated PSP in patients with pancreatic diseases, especially acute pancreatitis. Among non-pancreatic conditions, increased PSP was observed in gastric cancer, gallstone disease, liver cirrhosis, non-insulin-dependent diabetes, and peptic ulcers. Notably, patients with end-stage renal disease undergoing hemodialysis exhibited the highest serum PSP concentrations among the non-pancreatic conditions studied, likely due to the impaired renal clearance of PSP (Figure 2) [11].
To date, no published studies have reported the biological half-life (t1/2) of pancreatic stone protein, indicating a gap in the existing pharmacokinetic data. Subsequent research evaluated PSP levels across different age groups and health statuses. The PSP concentration in the general population was not influenced by gender and ranged from 1 to 99.4 ng/mL, with a median of 9.2 ng/mL. PSP varied significantly with age, increasing from a median of 2.6 ng/mL in very preterm newborns to 6.3 ng/mL in term newborns and 16.1 ng/mL in older children (p < 0.001). The PSP concentration also showed a significant rise by postnatal day three compared to levels measured immediately after delivery (p < 0.001). Strong correlations were observed between umbilical artery and vein samples (Spearman’s Rho 0.96, p < 0.001), and capillary heel-prick samples demonstrated a good agreement with venous samples for PSP [12]. A comprehensive summary of PSP levels across different populations and disease states, with comparisons to CRP and PCT, is presented in Table 1.

4.3. Multifaceted Roles of PSP in Beta Cell Regeneration, Diabetes, and Biomarker Potential

Research has provided important insights into the role of Reg protein, which encodes PSP, in beta cell regeneration and maintenance. Reg mRNA expression has been observed in acinar cells during beta cell regeneration following a partial pancreatectomy and the removal of subcutaneously transplanted insulinomas. This suggests that Reg protein in acinar cells may act paracrinally on islets or precursor cells, playing a potentially crucial role in maintaining the beta cell mass under normal conditions [13]. In experimental models, PSP treatments also reduced serum levels of pancreatic amylase, lactate dehydrogenase (LDH), and key inflammatory cytokines, including TNF-α and IL-6, compared with untreated models, demonstrating a clear protective effect [14].
Molecular comparisons provide additional insight into PSP’s functional characteristics. The amino-terminal 154 residues of PSP align with the asialoglycoprotein family, showing a 20% similarity to the human IgE receptor, indicating potential immunological or receptor interactions for PSP [15]. Furthermore, early studies posited that PSP’s homology to lectins might facilitate its binding to carbohydrates or carbohydrate moieties of proteins, highlighting a potential mechanism for PSP interactions in the body [16].
The expression of PSP-related proteins, particularly Reg 1 and Reg 2, is notably higher in diabetic db/db mice compared to wild-type mice, suggesting a potential link between PSP and inflammatory processes associated with diabetes. Both Reg 1 and Reg 2 can induce neutrophil activation, implicating these proteins in the diabetic inflammatory cascade [17]. Clinically, elevated PSP/Reg levels are consistently observed in diabetic patients, even in high-risk groups. Notably, PSP/Reg levels increase with diabetes duration and correlate with chronic complications, positioning PSP/Reg as a possible biomarker for patient stratification and outcome prediction in diabetes [18].
PSP/Reg has also been identified as a potential marker of endoplasmic reticulum (ER) stress in beta cells, particularly in Wolfram syndrome. During ER stress, PSP/Reg expression, translation, and secretion increase, likely aiding beta cell proliferation and survival. Thus, PSP/Reg may act as a circulating biomarker for beta cell ER stress, indicating disease progression [19,20].
Additionally, a recent study found that patients with type 2 diabetes mellitus have significantly elevated PSP/Reg Iα levels compared to nondiabetic individuals. In both diabetic and nondiabetic cohorts, the levels of PSP/Reg Iα were found to have an inverse correlation with the estimated glomerular filtration rate (eGFR) and a positive association with age, serum creatinine, and blood urea nitrogen. An ordinal logistic regression analysis highlighted a negative correlation between PSP/Reg Iα levels and kidney function, suggesting PSP/Reg 1α could indicate renal decline in diabetes [21].
These findings collectively emphasize the multifaceted roles of PSP/Reg proteins in pancreatic regeneration, immune modulation, inflammation, ER stress response, and kidney function, with implications for their use as biomarkers and therapeutic targets in diabetes and related disorders.

4.4. Roles of PSP in Renal Function, Tissue Regeneration, and Diabetes-Related Complications

PSP has been detected in both the urine and renal calculi of healthy individuals, as well as in elevated concentrations in the urine of patients with various renal diseases, including diabetic nephropathy and critically ill patients in intensive care [22]. Urinary PSP can be explained through two mechanisms. First, since PSP is a small protein (14–19 kDa), it can circulate in the blood and cross the glomerular basement membrane. Normally reabsorbed by proximal renal tubules, increased urinary PSP levels may indicate impaired renal tubular function. Alternatively, PSP may leak into the urine from injured renal tubular epithelial cells, indicating cellular damage within the kidneys [23].
Some patients with renal disease show urinary PSP that differs structurally from the form found in their blood, suggesting that PSP may also be synthesized within the kidneys and released upon renal injury. Moreover, Reg receptor mRNA has been identified in various tissues, such as the liver, kidney, and brain. This suggests that the Reg–Reg receptor signaling system may have functions extending beyond pancreatic beta cells [2].
In acute stress conditions such as myocardial infarction, the transcription of the Reg gene and its receptor is activated in the heart, highlighting the potential involvement of Reg proteins in heart tissue recovery [24]. PSP/Reg proteins also appear upregulated in tissue regeneration, with an increased expression observed following treatments like nicotinamide administration and a partial pancreatectomy [13]. PSP/Reg may act as a growth mediator, stimulating beta cell proliferation during tissue repair. Furthermore, during acute and chronic pancreatitis, expression is also significantly upregulated, suggesting it may serve as a stress-induced protective protein to counteract pancreatic injury [25].
Research conducted on acinar cells indicates that overexpression is associated with acinar cell differentiation, whereas the inhibition of Reg 1 results in a transition towards alpha or ductal cell phenotypes. This role in maintaining the cell lineage indicates that Reg 1 expression may be essential to prevent the dedifferentiation of pancreatic cells, supporting acinar and endocrine functions [26]. The progressive decline of acinar cells, and consequently of the pancreas, is associated with glucose intolerance and chronic pancreatitis-related islet failure, suggesting that Reg 1 plays a role in glucose regulation through its impact on beta cell function [27].
In diabetic kidney disease (DKD), serum PSP/Reg levels are significantly elevated compared to healthy individuals, patients with newly diagnosed type 2 diabetes mellitus, and diabetes patients without DKD. One study found that PSP/Reg concentrations positively correlate with glycated hemoglobin (HbA1c) and serum creatinine and negatively correlate with the eGFR, highlighting its potential as a biomarker for renal injury in diabetes [28]. Additionally, in a 2022 study, Reg 1α was identified as a promising diagnostic marker with high correlations to the urinary albumin–creatinine ratio and eGFR, demonstrating its utility for early DKD risk prediction [29].
Overall, PSP/Reg proteins appear to play essential roles in pancreatic, renal, and cardiac tissues, as well as in the cellular response to stress and injury. These proteins hold promise as biomarkers and therapeutic targets in diseases involving tissue damage, particularly in diabetes-related complications.

4.5. PSP as a Biomarker and Therapeutic Potential Across Cancer Types

Research highlights the diverse and context-dependent role of PSP and related Reg proteins in cancer biology. In pancreatic tumors, PSP is absent in adenocarcinoma extracts but present in normal tissue, while in pancreatic acinar cell carcinoma, PSP and Reg proteins may serve as markers of acinar differentiation [30]. Reg 1 is expressed in pancreatic, gastric, and colon adenocarcinomas but not in esophageal squamous carcinoma. In gastric cancer, its expression correlates with the tumor invasiveness, venous invasion, and a poorer prognosis in differentiated adenocarcinoma [31]. Reg 1α has also emerged as a predictor of chemotherapy responses, with positive cases showing an improved progression-free and overall survival. Interestingly, Reg 1α expression may appear after chemotherapy failure, suggesting a role in acquired resistance [32]. In pancreatic adenocarcinoma, Reg 1α has been incorporated into urine-based biomarker panels for early detection [33], while Reg 1α and Reg 1β also show potential as circulating biomarkers [34]. Beyond gastrointestinal cancers, Reg 1 expression influences the prognosis in head and neck squamous cell carcinoma [35] and genetic susceptibility in nasopharyngeal carcinoma [36]. Additional studies link Reg 1α to melanoma chemosensitivity [37] and a poor lung cancer prognosis [38]. Collectively, Reg proteins appear integral to tumor biology, serving as biomarkers of the aggressiveness, therapy response, and cancer risk.

4.6. Therapeutic and Diagnostic Implications of PSP in Gastric, Intestinal, and Inflammatory Disorders

A growing body of research highlights the critical role of Reg 1 in the response and adaptation of gastric and intestinal tissues to injury. In a study conducted on rats with aspirin-induced gastric injury, an increased Reg 1 expression was observed, suggesting that Reg 1 may play a vital role in helping the gastric epithelium adapt to repeated aspirin-induced damage. This aligns with Reg 1′s established associations with injury repair in the upper gastrointestinal tract, where it is thought to act as a mitogen or growth factor, promoting cellular growth and repair [39].
Additional findings have shown that Reg 1 expression also increases in response to indomethacin, a nonsteroidal anti-inflammatory drug (NSAID), with mRNA levels rising rapidly within six hours of administration and peaking just before the development of small intestinal ulcers. Mice lacking Reg 1 (Reg 1 knockout) experienced more severe indomethacin-induced intestinal injuries compared to their wild-type counterparts. Furthermore, the administration of recombinant Reg 1 inhibited the formation of these drug-induced injuries, with both morphological and biochemical analyses confirming its therapeutic effect. These findings suggest that Reg 1 could serve as a promising therapeutic agent for managing NSAID-induced small intestinal injuries [40].
Similarly, the Reg gene expression was significantly upregulated in the fundic mucosa during Helicobacter pylori infections, especially in cases of hypergastrinemia, where the Reg protein-positive cell count increased. Notably, Reg mRNA expression correlated closely with the severity of inflammation in the fundic mucosa. During H. pylori-induced gastritis, the gastric epithelial cells undergo continuous cycles of damage from inflammation and subsequent regeneration. This regenerative response appears to be mediated, in part, by the Reg gene activation, suggesting a close relationship between Reg gene expression, elevated serum gastrin levels, and the extent of mucosal inflammation during the H. pylori infection [41].
These findings underscore the potential role of Reg 1 as both a biomarker and a therapeutic target in gastrointestinal disorders, particularly those involving a mucosal injury and inflammation, such as drug-induced gastritis and H. pylori-associated gastritis.
Research increasingly suggests that Reg 1α gene expression is markedly upregulated in various gastrointestinal disorders, not only within ulcerative colitis (UC) and colitis-associated cancers but also in sporadic colon adenomas and cancers, as demonstrated by a real-time RT-PCR analysis [42]. Further studies indicate a substantial overexpression of Reg family mRNAs in colonic mucosa affected by Crohn’s disease (CD) and UC, with a strong association to tissue injury and repair mechanisms. This expression pattern, while prominent in inflammatory bowel disease (IBD), is not exclusive to it; for example, Reg protein expression is also observed in pseudomembranous colitis, indicating a broader role in inflammatory and reparative processes in the colon [43].
The examination of IBD patient samples from a research biobank revealed that metaplastic Paneth cells in both inflamed and noninflamed mucosal areas express Reg 1α, Reg 1 β, and Reg 3α mRNA. Notably, Reg 1α, which normally shows a limited expression, expands significantly to nearly all cells in the lower half of colonic crypts during active inflammation, suggesting a robust response linked to tissue repair in inflamed states [44].
In pediatric patients with symptoms of IBD, a study of ileal biopsy samples identified an elevated Reg 1α expression in the terminal ileum among those with CD. This contrasts with findings in adult CD patients, where the Reg 1α expression in the terminal ileum is reportedly downregulated, indicating potential differences in the pathogenesis of pediatric versus adult-onset CD. The high levels of Reg 1α expression observed in some pediatric CD cases raise concerns, as Reg 1α expression is also associated with cancer development, suggesting a possible increased risk of colorectal cancer in these patients. Early-onset CD has previously been linked to a heightened risk of colorectal cancer, highlighting the significance of this finding [45].

4.7. Reg 1α Overexpression and Autoimmune Implications in Sjögren’s Syndrome

The Reg 1α protein, typically expressed only in a limited number of ductal cells and not in acinar or interstitial cells of normal minor salivary glands, is notably overexpressed in the ductal cells of patients with Sjögren’s syndrome (SS). This pattern suggests that inflammation—whether autoimmune in nature or not—may be a key trigger for the overexpression of Reg 1α in various tissues, and investigating the Reg family gene expression in the minor salivary glands of SS patients and screening for anti-Reg 1α autoantibodies further supports this [3]. The research found that Reg 1α mRNA levels in the minor salivary glands of SS patients were significantly higher compared to controls, with Reg 1α protein prominently expressed in the ductal epithelial cells of those with SS. Additionally, 11% of SS patients showed the presence of anti-Reg 1α autoantibodies in their sera. Among those positive for these autoantibodies, all displayed Reg 1α expression in their minor salivary glands, whereas only 40% of those without the autoantibodies showed such expression. The group with anti-Reg 1α autoantibodies also had significantly reduced saliva secretion and more severe ductal gland damage, as reflected by Rubin–Holt grade 4 scores in sialography. This evidence suggests that autoimmunity against Reg 1α could contribute to the degeneration of ductal epithelial cells in primary Sjögren’s syndrome [46].

4.8. Emerging Role of PSP in Alzheimer’s Disease and Neurodegenerative Pathologies

Research on the central nervous system suggests that PSP plays a dynamic role in neurodevelopment and neurodegeneration. PSP levels are elevated in Alzheimer’s disease (AD) brains compared to controls, while healthy brains show low but detectable immunoreactivity [47]. A unique 0.6 kb PSP transcript, found only in AD brains, points to an abnormal expression or possible mutation [48]. PSP is highly expressed in fetal and infant brains but declines with age, indicating developmental regulation. Overexpression during preclinical AD stages hints at a role in disease onset [49]. PSP deposits are also observed in other neurodegenerative disorders, suggesting a contribution to the amyloid pathology [50]. Studies in aging mouse lemurs indicate that accumulation may reflect chronic inflammation rather than AD specifically, and in vitro work shows that the proteolytic processing of glycosylated Reg 1α, a PSP variant, is influenced by calpain-2, warranting further investigation into its role in neurodegeneration [51,52].

4.9. Serum PSP as a Biomarker in Healthy and Complicated Pregnancies

Serum PSP levels were measured using a specific enzyme-linked immunosorbent assay in healthy pregnant women. The mean reference PSP values in singleton pregnancies were 7.9 ± 2.6 ng/mL, while women with multiple pregnancies showed significantly higher levels at 9.17 ± 3.06 ng/mL. Levels increased progressively across trimesters, with values in the first trimester being 6.94 ± 2.53 ng/mL, the second trimester being 7.42 ± 2.21 ng/mL, and the third trimester being 8.33 ± 2.68 ng/mL. No correlation was observed between PSP levels and maternal characteristics or pre-existing medical conditions. PSP values in healthy pregnancies (4–12 ng/mL) aligned closely with those of the general healthy population (8–16 ng/mL) [53].
The role of PSP as a diagnostic biomarker was evaluated for pregnancy-related conditions, such as preeclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, the preterm premature rupture of membranes (PPROM), intraamniotic infections, and COVID-19. Women with preeclampsia or HELLP syndrome exhibited significantly higher PSP levels compared to healthy singleton pregnancies. In contrast to that, no significant difference was found in PSP levels between women with PPROM and healthy singleton pregnancies. PSP levels in women with or without intraamniotic infections were similar. Lastly, regarding COVID-19, PSP levels in pregnant women infected with COVID-19 were comparable to healthy singleton pregnancies. PSP was significantly elevated in preeclampsia and HELLP syndrome, suggesting its potential as a biomarker for these disorders. However, it showed no diagnostic utility for conditions such as PPROM, intraamniotic infections, or COVID-19 in pregnancy [54].

4.10. Reg 1α as a Key Mediator in Orofacial Clefting

There is research on transgenic Drosophila models that associated Reg 1α as a key regulator in orofacial clefting (OFC). OFC E-cadherin variants were found to disrupt tissue shaping and migration through a Reg 1α-dependent mechanism. Transcriptomic analyses revealed distinct profiles linked to OFC, identifying Reg 1α as a critical mediator. The RNA interference targeting Reg 1α altered cell migration patterns, resulting in slower wound closure and less coordinated leading-edge movement. This underscores the importance of Reg 1α in craniofacial development and its potential in addressing structural birth defects like OFC [55].

4.11. Key Roles of PSP in Antimicrobial Defense and Protection Against Intestinal Pathogens

PSP demonstrates significant antimicrobial activity by inducing bacterial aggregation without directly inhibiting bacterial growth. This activity is enhanced by trypsin, which facilitates bacterial control and helps prevent infection [56,57].
Colonic biopsy samples during acute and convalescent Entamoeba histolytica infections highlighted a sharp upregulation of Reg 1α and Reg 1β genes in the human intestine during acute disease. A microarray analysis showed 7.4-fold and 10.7-fold increases in Reg 1α and Reg 1β expression, respectively (p = 0.003 and p = 0.006). These findings were corroborated by reverse transcriptase quantitative polymerase chain reactions (RT-qPCRs) and immunohistochemistry, which identified a heightened Reg 1 protein expression in colonic crypt epithelial cells during acute amebiasis. Given that Reg 1 proteins are antiapoptotic and pro-proliferative, further experiments revealed that intestinal epithelial cells from Reg 1 knockout mice were more vulnerable to both spontaneous and parasite-induced apoptosis (p = 0.03). These results suggest that Reg 1α and Reg 1β play a protective role during amebiasis by preventing E. histolytica-induced epithelial cell apoptosis [4].
In 2013, research on gnotobiotic piglets provided the first in vivo evidence that Reg 1α acts as a C-type lectin, demonstrating adherence to Shiga toxin-producing Escherichia coli. This study confirmed its role in innate immune defense, bacterial aggregation, and antiapoptotic activity [58].
PSP’s secondary metabolites can exhibit antimicrobial properties by inhibiting Gram-negative bacteria with lipopolysaccharides. Additionally, they hinder beta-lactamase enzyme production by Staphylococcus aureus. Consistent with prior findings, PSP was particularly effective against bacterial species such as E. coli and Pseudomonas aeruginosa [59].

4.12. PSP as Biomarker in Sepsis Diagnosis, Prognosis, and Critical Care Applications

It was demonstrated in mouse and rat models that the pancreas reacts to remote lesions and septic insults with increased PSP synthesis [60]. Recently, a hypothetical model was proposed, in which PSP synthesis increased as part of an acute-phase pancreatic response due to innate immune activation. This paradigm may suggest that PSP could contribute to organ failure, sepsis, and septic shock and that PSP modulation could impact the sepsis pathophysiology [5].
In 2012, Que et al. [61] studied septic patients requiring ICU (intensive care unit) management by measuring PSP levels within 24 h of ICU admission. Results suggested that PSP could serve as a prognostic biomarker to stratify the sepsis severity and mortality risk, demonstrating its utility in identifying patients at the highest risk of death [61]. Further research has shown that PSP levels rise quickly in the bloodstream during sepsis, potentially providing an early warning signal up to 72 h before clinical deterioration becomes evident with conventional markers such as CRP or PCT [62].
Separately, in a retrospective analysis of 101 patients with ventilator-associated pneumonia, PSP levels were higher in nonsurvivors, reflecting organ dysfunction and aiding in distinguishing survivors from nonsurvivors [63]. Another study demonstrated that mechanically ventilated patients who developed sepsis had significantly elevated PSP levels compared with those who did not, highlighting its potential as an early and severity-related biomarker in this population. Importantly, PSP levels were generally elevated across the cohort, even in the absence of sepsis, reflecting the burden of critical illness and the effects of mechanical ventilation [64]. However, a 2023 study found that PSP values alone or in combination with other markers did not enhance diagnostic accuracy for ventilator-associated pneumonia [65].
A study involving 126 septic patients compared PSP, sCD25, and PCT as sepsis biomarkers, showing similar high accuracies (area under the curve > 0.8). PSP effectively differentiated sepsis from noninfective illnesses in critical care, highlighting its diagnostic value alongside other markers [66].
Related to neonatal sepsis, a multicenter 2012 study of 137 infants showed higher PSP levels in infected infants versus uninfected ones, predicting early-onset sepsis independently of PCT (p < 0.001) [67]. Rass et al. (2016) confirmed PSP’s high negative predictive value (89.3%) in ruling out sepsis, potentially limiting unnecessary treatments [68,69]. Similarly, PSP, combined with PCT and CRP, was identified as a valuable biomarker for risk stratification in pediatric sepsis [70]. PSP levels significantly differentiated sepsis from sterile inflammation, with an optimal cutoff of 167 ng/mL yielding a good sensitivity and specificity. However, these results should be confirmed in larger pediatric populations [71].
Additionally, PSP levels correlated with the sepsis severity in critically ill adults and children, outperforming CRP and PCT in predicting outcomes. However, studies noted PSP’s limitations in specific contexts, such as trauma ICUs and fungal infections, emphasizing its role as a general inflammatory marker rather than being sepsis-specific [72,73].
In view of surgery, postoperative PSP levels were linked to infection, with higher levels observed after a sternotomy versus minimally invasive surgery. PSP also distinguished septic from nonseptic burn patients, rising days before clinical signs of sepsis [74].
PSP proved to be a useful prognostic biomarker in severe COVID-19, reflecting both viral inflammation and secondary sepsis [75]. Considering COVID-19, PSP outperformed PCT and CRP as a biomarker for disease progression. Its utility extended to predicting mortality over 90 days and the ICU admission risk [76].
Meta-analyses corroborated PSP’s diagnostic superiority over CRP and equivalence to PCT [74]. Also, the combination of PSP with CRP further enhanced its accuracy. Contrary to that, results of a meta-analysis including 678 patients showed PSP’s predictive value for ICU mortality and infection severity as significant, but combinations with other markers did not enhance the diagnostic power [77]. More recently, a prospective ICU cohort study of patients admitted with severe sepsis or septic shock compared PSP with established biomarkers, including CRP, PCT, and inflammatory cytokines (IL-6, IL-8, IL-10)—as well as clinical severity scores (APACHE II, SAPS II/III, SOFA). In this context, PSP demonstrated a strong predictive performance for in-hospital mortality, reinforcing its diagnostic utility alongside other established markers [64].
As far as the economic side is concerned, rapid PSP testing reduced healthcare costs in emergency and ICU settings by improving diagnostic specificity and sensitivity, supporting its integration into routine sepsis care [78].

4.13. Future Directions and Limitations

Several studies emphasized PSP’s limitations in complex patient populations, such as those with oncological or autoimmune conditions, and the need for additional research to validate its clinical applications. Emerging findings suggest PSP may act as a biomarker for general inflammation rather than sepsis-specific processes [5,79,80]. Future research priorities include standardizing PSP assays and establishing diagnostic thresholds, validating its utility in large, multicenter cohorts across diverse populations, integrating PSP with established biomarkers such as CRP and PCT to enhance composite risk stratification, and exploring its potential therapeutic role in regulating inflammation and promoting tissue repair. Advancing these efforts will be essential to establish PSP as a reliable and widely applicable clinical tool.

5. Conclusions

In summary, PSP shows considerable potential as a biomarker for sepsis and critical illness across diverse patient populations. It may aid in stratifying the infection severity and guiding therapeutic decisions, though further research is required to clarify its clinical applicability and context-specific limitations. Beyond its diagnostic and prognostic value, evidence from this study also indicates that PSP may exert direct protective effects on pancreatic tissue under septic conditions.

6. Limitations of the Review Process

Despite efforts to ensure comprehensiveness, several limitations should be acknowledged regarding the review process. The literature search was conducted exclusively in the PubMed database. Although PubMed is a comprehensive and widely used biomedical source, relevant studies indexed in other databases, such as Embase, Scopus, or Web of Science, may have been missed. Also, only articles published in English were included. A formal risk of bias assessment of included studies was not conducted. As a result, the methodological quality and potential limitations of individual studies were not systematically evaluated. Due to the heterogeneity of study designs, populations, and outcome measures, a meta-analysis was not performed. Instead, findings were summarized narratively, which may limit the strength of the conclusions.

Author Contributions

N.V.V. and L.Z. contributed to the conception and design of the review, as well as to the analysis and interpretation of the literature. N.V.V., L.Š., and P.S. drafted the initial version of the manuscript, while D.D. and L.Z. provided critical revisions for important intellectual content. All authors agree to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

This review did not generate any new data. All information analyzed and discussed in this review is derived from previously published studies, primarily sourced from the PubMed database. These sources are publicly available, cited appropriately throughout the text, and fully listed in the references.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
PSPpancreatic stone protein
PTPpancreatic thread protein
Regregenerating

References

  1. De Caro, A.; Luc, T.; Lafont, H.; Lombardo, D.; Sarles, H. The molecular characteristics of a human pancreatic acidic phosphoprotein that inhibits calcium carbonate crystal growth. Biochem. J. 1984, 222, 669–677. [Google Scholar] [CrossRef] [PubMed]
  2. Kobayashi, S.; Akiyama, T.; Nata, K.; Abe, M.; Tajima, M.; Shervani, N.J.; Unno, M.; Matsuno, S.; Sasaki, H.; Takasawa, S.; et al. Identification of a receptor for Reg (regenerating gene) protein, a pancreatic β-cell regeneration factor. J. Biol. Chem. 2000, 275, 10723–10726. [Google Scholar] [CrossRef] [PubMed]
  3. Kimura, T.; Fukui, H.; Sekikawa, A.; Yamagishi, H.; Ichikawa, K.; Tomita, S.; Fujii, S.; Imura, J.; Kawamata, H.; Chiba, T.; et al. Involvement of REG Iα protein in the regeneration of ductal epithelial cells in the minor salivary glands of patients with Sjögren’s syndrome. Clin. Exp. Immunol. 2009, 155, 16–20. [Google Scholar] [CrossRef] [PubMed]
  4. Peterson, K.M.; Guo, X.; Elkahloun, A.G.; Mondal, D.; Bardhan, P.K.; Sugawara, A.; Duggal, P.; Haque, R.; Petri, W.A. The expression of REG 1A and REG 1B is increased during acute amebic colitis. Parasitol. Int. 2011, 60, 296–300. [Google Scholar] [CrossRef] [PubMed]
  5. Ventura, F.; Tissières, P. The Possible Pathophysiological Role of Pancreatic Stone Protein in Sepsis and Its Potential Therapeutic Implication. Biomedicines 2024, 12, 1790. [Google Scholar] [CrossRef]
  6. De Caro, A.M.; Bonicel, J.J.; Rouimi, P.; De Caro, J.D.; Sarles, H.; Rovery, M. Complete amino acid sequence of an immunoreactive form of human pancreatic stone protein isolated from pancreatic juice. Eur. J. Biochem. 1987, 168, 201–205. [Google Scholar] [CrossRef]
  7. Schmiegel, W.; Burchert, M.; Kalthoff, H.; Roeder, C.; Biitzow, G.; Grimm, H.; Kremer, B.; Schreiber, H.-W.; Thiele, H.-G.; Greten, H. Immunochemical Characterization and Quantitative Distribution of Pancreatic Stone Protein in Sera and Pancreatic Secretions in Pancreatic Disorders. Gastroenterology 1990, 99, 1421–1430. [Google Scholar] [CrossRef]
  8. Bimmler, D.; Graf, R.; Scheele, G.A.; Frick, T.W. Pancreatic stone protein (lithostathine), a physiologically relevant pancreatic calcium carbonate crystal inhibitor? J. Biol. Chem. 1997, 272, 3073–3082. [Google Scholar] [CrossRef]
  9. Gross, J.; Carlson, R.I.; Brauer, A.W.; Margolies, M.N.; Warshaw, A.L.; Wands, J.R. Isolation, characterization, and distribution of an unusual pancreatic human secretory protein. J. Clin. Investig. 1985, 76, 2115–2126. [Google Scholar] [CrossRef]
  10. Varilh, M.; Acquatella-Tran Van Ba, I.; Silhol, M.; Nieto-Lopez, F.; Moussaed, M.; Lebart, M.C.; Bovolenta, P.; Verdier, J.M.; Rossel, M.; Marcilhac, A.; et al. Reg-1α Promotes Differentiation of Cortical Progenitors via Its N-Terminal Active Domain. Front. Cell Dev. Biol. 2020, 8, 681. [Google Scholar] [CrossRef]
  11. Hayakawa, T.; Kondo, T.; Shibata, T.; Kitagawa, M.; Sakai, Y.; Sobajima, H.; Tanikawa, M.; Nakae, Y.; Hayakawa, S.; Katsuzaki, T.; et al. Serum Pancreatic Stone Protein in Pancreatic Diseases. Int. J. Pancreatol. 1993, 13, 97–103. [Google Scholar] [CrossRef]
  12. Schlapbach, L.J.; Giannoni, E.; Wellmann, S.; Stocker, M.; Ammann, R.A.; Graf, R. Normal values for pancreatic stone protein in different age groups. BMC Anesth. 2015, 15, 168. [Google Scholar] [CrossRef]
  13. Watanabe, T.; Yonemurat, Y.; Yonekura, H.; Suzuki, Y.; Miyashita, H.; Sugiyamat, K.; Moriizumi, S.; Unno, M.; Tanakat, O.; Kondot, H.; et al. Pancreatic beta-cell replication and amelioration of surgical diabetes by Reg protein (Reg gene/diabetes mellitus/Isets of Langerhans/growth factor). Proc. Natl. Acad. Sci. USA 1994, 91, 3589–3592. [Google Scholar] [CrossRef]
  14. Liu, P.; Xiao, Z.; Lu, X.; Zhang, X.; Huang, J. Pancreatic stone protein inhibits pyroptosis of pancreatic acinar cells in sepsis-associated pancreatic injury. Front. Med. 2025, 12, 1566728. [Google Scholar] [CrossRef] [PubMed]
  15. Petersen, T.E. The amino-terminal domain of thrombomodulin and pancreatic stone protein are homologous with lectins. FEBS Lett. 1988, 231, 51–53. [Google Scholar] [CrossRef] [PubMed]
  16. Patthy, L. Homology of human pancreatic stone protein with animal lectins. Biochem. J. 1988, 253, 309.2–311. [Google Scholar] [CrossRef] [PubMed]
  17. Pérez-Vázquez, V.; Guzmán-Flores, J.M.; Mares-Álvarez, D.; Hernández-Ortiz, M.; Macías-Cervantes, M.H.; Ramírez-Emiliano, J.; Encarnación-Guevara, S. Differential proteomic analysis of the pancreas of diabetic db/db mice reveals the proteins involved in the development of complications of diabetes mellitus. Int. J. Mol. Sci. 2014, 15, 9579–9593. [Google Scholar] [CrossRef]
  18. Yang, J.; Li, L.; Raptis, D.; Li, X.; Li, F.; Chen, B.; He, J.; Graf, R.; Sun, Z. Pancreatic stone protein/regenerating protein (PSP/reg): A novel secreted protein up-regulated in type 2 diabetes mellitus. Endocrine 2015, 48, 856–862. [Google Scholar] [CrossRef]
  19. Stone, S.; Abreu, D.; Mahadevan, J.; Asada, R.; Kries, K.; Graf, R.; Marshall, B.A.; Hershey, T.; Urano, F. Pancreatic stone protein/regenerating protein is a potential biomarker for endoplasmic reticulum stress in beta cells. Sci. Rep. 2019, 9, 5199. [Google Scholar] [CrossRef]
  20. Cui, C.; Fu, M.; Gao, B. Procalcitonin and pancreatic stone protein function as biomarkers in early diagnosis of pediatric acute osteomyelitis. Med. Sci. Monit. 2017, 23, 5211–5217. [Google Scholar] [CrossRef]
  21. Zhu, H.; Zhu, X.; Lin, H.; Liu, D.; Dai, Y.; Su, X.; Li, L. Association of Serum PSP/REG i with Renal Function in Type 2 Diabetes Mellitus. J. Diabetes Res. 2020, 2020, 9787839. [Google Scholar] [CrossRef]
  22. Tatemichi, N.; Kato, M.; Hayakawa, S.; Hayakawa, T.; Naruse, S.; Kitagawa, M.; Sobajima, H.; Nakae2, Y. Immunological Characterization of Pancreatic Stone Protein in Human Urine. J. Clin. Lab. Anal. 1994, 8, 76–80. [Google Scholar] [CrossRef] [PubMed]
  23. Sobajima, H.; Niwa, T.; Shikano, M.; Naruse, S.; Kitagawa, M.; Nakae, Y.; Ishiguro, H.; Kondo, T.; Hayakawa, T. Urinary Excretion of Pancreatic Stone Protein in Diabetic Nephropathy. Intern. Med. 1998, 37, 500–503. [Google Scholar] [CrossRef]
  24. Kiji, T.; Dohi, Y.; Takasawa, S.; Okamoto, H.; Nonomura, A.; Taniguchi, S.; Oka-moto, H. Activation of regenerating gene Reg in rat and human hearts in response to acute stress. Am. J. Physiol. Heart Circ. Physiol. 2005, 289, 277–284. [Google Scholar] [CrossRef] [PubMed]
  25. Fortunato, F.; Deng, X.; Gates, L.K.; McClain, C.J.; Bimmler, D.; Graf, R.; Whitcomb, D.C. Pancreatic response to endotoxin after chronic alcohol exposure: Switch from apoptosis to necrosis? Am. J. Physiol.-Gastrointest. Liver Physiol. 2006, 290, G232–G241. [Google Scholar] [CrossRef]
  26. Sanchez, D.; Mueller, C.M.; Zenilman, M.E. Pancreatic Regenerating Gene I and Acinar Cell Differentiation Influence on Cellular Lineage. Pancreas 2009, 38, 572–577. [Google Scholar] [CrossRef]
  27. Bluth, M.; Mueller, C.M.; Pierre, J.; Callender, G.; Kandil, E.; Viterbo, D.; Fu, S.L.; Sugawara, A.; Okamoto, H.; Zenilman, M.E. Pancreatic Regenerating Protein I in Chronic Pancreatitis and Aging Implications for New Therapeutic Approaches to Diabetes. Pancreas 2008, 37, 386–395. [Google Scholar] [CrossRef] [PubMed]
  28. Li, L.; Jia, D.; Graf, R.; Yang, J. Elevated serum level of pancreatic stone protein/regenerating protein (PSP/reg) is observed in diabetic kidney disease. Oncotarget 2017, 8, 38145. [Google Scholar] [CrossRef]
  29. Wang, X.; Wu, H.; Yang, G.; Xiang, J.; Xiong, L.; Zhao, L.; Liao, T.; Zhao, X.; Kang, L.; Yang, S.; et al. REG1A and RUNX3 Are Potential Biomarkers for Predicting the Risk of Diabetic Kidney Disease. Front. Endocrinol. 2022, 13, 935796. [Google Scholar] [CrossRef]
  30. Hoorens, A.; Lemoine, N.R.; Mclellan, E.; Morohoshi, T.; Kamisawa, T.; Heitz, P.U.; Stamm, B.; Ruschoff, J.; Wiedenmann, B.; Kloppel, G. Pancreatic Acinar Cell Carcinoma an Analysis of Cell Lineage Markers, p53 Expression, and Ki-ras Mutation. Am. J. Pathol. 1993, 143, 685. [Google Scholar]
  31. Yonemura, Y.; Sakurai, S.; Yamamoto, H.; Endou, Y.; Kawamura, T.; Bandou, E.; Elnemr, A.; Sugiyama, K.; Sasaki, T.; Akiyama, T.; et al. REG gene expression is associated with the infiltrating growth of gastric carcinoma. Cancer 2003, 98, 1394–1400. [Google Scholar] [CrossRef]
  32. Sekikawa, A.; Fukui, H.; Zhang, X.; Maruo, T.; Tsumura, T.; Okabe, Y.; Wakasa, T.; Osaki, Y.; Chiba, T.; Tomita, T.; et al. REG Iα is a biomarker for predicting response to chemotherapy with S-1 plus cisplatin in patients with unresectable stage IV gastric cancer. Br. J. Cancer 2013, 108, 395–401. [Google Scholar] [CrossRef]
  33. Radon, T.P.; Massat, N.J.; Jones, R.; Alrawashdeh, W.; Dumartin, L.; Ennis, D.; Duffy, S.W.; Kocher, H.M.; Pereira, S.P.; Guarner, L.; et al. Identification of a three-biomarker panel in urine for early detection of pancreatic adenocarcinoma. Clin. Cancer Res. 2015, 21, 3512–3521. [Google Scholar] [CrossRef]
  34. Lyu, J.; Jiang, M.; Zhu, Z.; Wu, H.; Kang, H.; Hao, X.; Cheng, S.; Guo, H.; Shen, X.; Wu, T.; et al. Identification of biomarkers and potential therapeutic targets for pancreatic cancer by proteomic analysis in two prospective cohorts. Cell Genom. 2024, 4, 100561. [Google Scholar] [CrossRef] [PubMed]
  35. Aboshanif, M.; Kawasaki, Y.; Omori, Y.; Suzuki, S.; Honda, K.; Motoyama, S.; Ishikawa, K. Prognostic role of regenerating gene-I in patients with stage-IV head and neck squamous cell carcinoma. Diagn. Pathol. 2016, 11, 79. [Google Scholar] [CrossRef] [PubMed]
  36. Xing, H.; Chen, X.; Sun, H.; Han, Y.; Ding, L.; Chen, X. Association of regenerating gene 1A single-nucleotide polymorphisms and nasopharyngeal carcinoma susceptibility in southern Chinese population. Eur. Arch. Oto-Rhino-Laryngol. 2020, 277, 221–226. [Google Scholar] [CrossRef] [PubMed]
  37. Sato, Y.; Marzese, D.M.; Ohta, K.; Huang, S.K.; Sim, M.S.; Chong, K.; Hoon, D.S.B. Epigenetic regulation of REG1A and chemosensitivity of cutaneous melanoma. Epigenetics 2013, 8, 1043–1052. [Google Scholar] [CrossRef]
  38. Kimura, M.; Naito, H.; Tojo, T.; Itaya-Hironaka, A.; Dohi, Y.; Yoshimura, M.; Nakagawara, K.I.; Takasawa, S.; Taniguchi, S. REG Iα gene expression is linked with the poor prognosis of lung adenocarcinoma and squamous cell carcinoma patients via discrete mechanisms. Oncol. Rep. 2013, 30, 2625–2631. [Google Scholar] [CrossRef]
  39. Alderman, B.M.; Ulaganathan, M.; Judd, L.M.; Howlett, M.; Parker, L.M.; Yeomans, N.D.; Giraud, A.S. Insights into the Mechanisms of Gastric Adaptation to Aspirin-Induced Injury: A Role for Regenerating Protein but Not Trefoil Peptides. Lab. Investig. 2003, 83, 1415–1425. [Google Scholar] [CrossRef]
  40. Imaoka, H.; Ishihara, S.; Kazumori, H.; Kadowaki, Y.; Monowar Aziz, M.; Binte Rahman, F.; Ose, T.; Fukuhara, H.; Takasawa, S.; Kinoshita, Y. Exacerbation of indomethacin-induced small intestinal injuries in Reg I-knockout mice. Am. J. Physiol. Gastrointest. Liver Physiol. 2010, 299, 311–319. [Google Scholar] [CrossRef]
  41. Fukui, H.; Franceschi, F.; Penland, R.L.; Sakai, T.; Sepulveda, A.R.; Fujimori, T.; Terano, A.; Chiba, T.; Genta, R.M. Effects of Helicobacter pylori Infection on the Link between Regenerating Gene Expression and Serum Gastrin Levels in Mongolian Gerbils. Lab. Investig. 2003, 83, 1777–1786. [Google Scholar] [CrossRef]
  42. Sekikawa, A.; Fukui, H.; Fujii, S.; Nanakin, A.; Kanda, N.; Uenoyama, Y.; Sawabu, T.; Hisatsune, H.; Kusaka, T.; Ueno, S.; et al. Possible role of REG Iα protein in ulcerative colitis and colitic cancer. Gut 2005, 54, 1437–1444. [Google Scholar] [CrossRef]
  43. Van Beelen Granlund, A.; Beisvag, V.; Torp, S.H.; Flatberg, A.; Kleveland, P.M.; Østvik, A.E.; Waldum, H.L.; Sandvik, A.K. Activation of REG family proteins in colitis. Scand. J. Gastroenterol. 2011, 46, 1316–1323. [Google Scholar] [CrossRef] [PubMed]
  44. Van Beelen Granlund, A.; Østvik, A.E.; Brenna, Ø.; Torp, S.H.; Gustafsson, B.I.; Sandvik, A.K. REG gene expression in inflamed and healthy colon mucosa explored by in situ hybridisation. Cell Tissue Res. 2013, 352, 639–646. [Google Scholar] [CrossRef]
  45. Sim, W.H.; Wagner, J.; Cameron, D.J.; Catto-Smith, A.G.; Bishop, R.F.; Kirkwood, C.D. Expression profile of genes involved in pathogenesis of pediatric Crohn’s disease. J. Gastroenterol. Hepatol. 2012, 27, 1083–1093. [Google Scholar] [CrossRef]
  46. Yoshimoto, K.; Fujimoto, T.; Itaya-Hironaka, A.; Miyaoka, T.; Sakuramoto-Tsuchida, S.; Yamauchi, A.; Takeda, M.; Kasai, T.; Nakagawara, K.; Nonomura, A.; et al. Involvement of autoimmunity to REG, a regeneration factor, in patients with primary Sjögren’s syndrome. Clin. Exp. Immunol. 2013, 174, 1–9. [Google Scholar] [CrossRef]
  47. Ozturkt, M.; De, S.M.; Montet, L.A.; Gross, J.; Wandst, J.R. Elevated levels of an exocrine pancreatic secretory protein in Alzheimer disease brain (pancreatic thread protein/monoclonal antibodies/immunoradiometric assays/Down syndrome). Proc. Natl. Acad. Sci. USA 1989, 86, 419–423. [Google Scholar] [CrossRef]
  48. De La Monte, S.M.; Ozturk, M.; Wands, J.R. Rapid Publication Enhanced Expression of an Exocrine Pancreatic Protein in Alzheimer’s Disease and the Developing Human Brain. J. Clin. Investig. 1990, 86, 1004–1013. [Google Scholar] [CrossRef]
  49. Duplan, L.; Michel, B.; Boucraut, J.; Barthellémy, S.; Desplat-Jego, S.; Marin, V.; Gambarelli, D.; Bernard, D.; Berthézène, P.; Alescio-Lautier, B.; et al. Lithostathine and pancreatitis-associated protein are involved in the very early stages of Alzheimer’s disease. Neurobiol. Aging 2001, 22, 79–88. [Google Scholar] [CrossRef] [PubMed]
  50. Laurine, E.; Grégoire, C.; Fändrich, M.; Engemann, S.; Marchal, S.; Thion, L.; Mohr, M.; Monsarrat, B.; Michel, B.; Dobson, C.M.; et al. Lithostathine Quadruple-helical Filaments Form Proteinase K-resistant Deposits in Creutzfeldt-Jakob Disease. J. Biol. Chem. 2003, 278, 51770–51778. [Google Scholar] [CrossRef] [PubMed]
  51. Marchal, S.; Givalois, L.; Verdier, J.M.; Mestre-Francés, N. Distribution of lithostathine in the mouse lemur brain with aging and Alzheimer’s-like pathology. Neurobiol. Aging 2012, 33, 431.e15–431.e25. [Google Scholar] [CrossRef]
  52. Lebart, M.C.; Trousse, F.; Valette, G.; Torrent, J.; Denus, M.; Mestre-Frances, N.; Marcilhac, A. Reg-1α, a New Substrate of Calpain-2 Depending on Its Glycosylation Status. Int. J. Mol. Sci. 2022, 23, 8591. [Google Scholar] [CrossRef]
  53. Vonzun, L.; Brun, R.; Gadient-Limani, N.; Schneider, M.A.; Reding, T.; Graf, R.; Limani, P.; Ochsenbein-Kölble, N. Serum Pancreatic Stone Protein Reference Values in Healthy Pregnant Women: A Prospective Cohort Study. J. Clin. Med. 2023, 12, 3200. [Google Scholar] [CrossRef]
  54. Brun, R.; Vonzun, L.; Cliffe, B.; Gadient-Limani, N.; Schneider, M.A.; Reding, T.; Graf, R.; Limani, P.; Ochsenbein-Kölble, N. The Role of Pancreatic Stone Protein (PSP) as a Biomarker of Pregnancy-Related Diseases. J. Clin. Med. 2023, 12, 4428. [Google Scholar] [CrossRef]
  55. Pereira, J.; Melo, S.; Ferreira, R.M.; Carneiro, P.; Yang, V.; Maia, A.F.; Carvalho, J.; Figueiredo, C.; Machado, J.C.; Morais-de-Sá, E.; et al. E-cadherin variants associated with oral facial clefts trigger aberrant cell motility in a REG1A-dependent manner. Cell Commun. Signal. 2024, 22, 152. [Google Scholar] [CrossRef]
  56. Medveczky, P.; Szmola, R.; Sahin-Tóth, M. Proteolytic activation of human pancreatitis-associated protein is required for peptidoglycan binding and bacterial aggregation. Biochem. J. 2009, 420, 335–343. [Google Scholar] [CrossRef] [PubMed]
  57. Iovanna, J.; Frigerio, J.M.; Dusetti, N.; Ramare, F.; Raibaud, P.; Dagorn, J.C. Lithostathine, an Inhibitor of CaCO, Crystal Growth in Pancreatic Juice, Induces Bacterial Aggregation. Pancreas 1993, 8, 647–653. [Google Scholar] [CrossRef] [PubMed]
  58. Pieper, R.; Zhang, Q.; Clark, D.J.; Parmar, P.P.; Alami, H.; Suh, M.J.; Kuntumalla, S.; Braisted, J.C.; Huang, S.T.; Tzipori, S. Proteomic View of Interactions of Shiga Toxin-Producing Escherichia coli with the Intestinal Environment in Gnotobiotic Piglets. PLoS ONE 2013, 8, e66462. [Google Scholar] [CrossRef] [PubMed]
  59. Mohammed, S.J.; Al-Musawi, A.T.; Al-Fraji, A.S.; Kareem, H.S. Comparison of three culture media in assessing the sensitivity of antibiotics to common foodborne microorganisms. J. Med. Life 2022, 15, 645–649. [Google Scholar] [CrossRef]
  60. Reding, T.; Palmiere, C.; Pazhepurackel, C.; Schiesser, M.; Bimmler, D.; Schlegel, A.; Süss, U.; Steiner, S.; Mancina, L.; Seleznik, G.; et al. The pancreas responds to remote damage systemic stress by secretion of the pancreatic secretory proteins PSP/regI and PAP/regIII. Oncotarget 2017, 8, 30162. [Google Scholar] [CrossRef]
  61. Que, Y.A.; Delodder, F.; Guessous, I.; Graf, R.; Bain, M.; Calandra, T.; Liaudet, L.; Eggimann, P. Pancreatic stone protein as an early biomarker predicting mortality in a prospective cohort of patients with sepsis requiring ICU management. Crit. Care 2012, 16, R114. [Google Scholar] [CrossRef] [PubMed]
  62. Kouroupis, D.; Zarras, C.; Koufakis, T.; Terzaki, M.; Pateinakis, P.; Chalvantzis, A.; Mpani, K.; Issa, A.; Soukiouroglou, P.; Sarvani, A.; et al. Pancreatic stone protein levels accurately predict severity in sepsis of various causes earlier than other biomarkers. J. Microbiol. Methods 2025, 232–234, 107129. [Google Scholar] [CrossRef]
  63. Boeck, L.; Graf, R.; Eggimann, P.; Pargger, H.; Raptis, D.A.; Smyrnios, N.; Thakkar, N.; Siegemund, M.; Rakic, J.; Tamm, M.; et al. Pancreatic stone protein: A marker of organ failure and outcome in ventilator-associated pneumonia. Chest 2011, 140, 925–932. [Google Scholar] [CrossRef] [PubMed]
  64. Belletti, A.; Bonizzoni, M.A.; Labanca, R.; Osenberg, P.; Bugo, S.; Pontillo, D.; Pieri, M.; Landoni, G.; Zangrillo, A.; Scandroglio, A.M. Pancreatic Stone Protein as Sepsis Biomarker in Patients Requiring Mechanical Circulatory Support: A Pilot Observational Study. J. Cardiothorac. Vasc. Anesth. 2025, 39, 1229–1235. [Google Scholar] [CrossRef]
  65. Ceccato, A.; Camprubí-Rimblas, M.; Bos, L.D.J.; Povoa, P.; Martin-Loeches, I.; Forné, C.; Areny-Balagueró, A.; Campaña-Duel, E.; Morales-Quinteros, L.; Quero, S.; et al. Evaluation of the Kinetics of Pancreatic Stone Protein as a Predictor of Ventilator-Associated Pneumonia. Biomedicines 2023, 11, 2676. [Google Scholar] [CrossRef]
  66. Llewelyn, M.J.; Berger, M.; Gregory, M.; Ramaiah, R.; Taylor, A.L.; Curdt, I.; Lajaunias, F.; Graf, R.; Blincko, S.J.; Drage, S.; et al. Sepsis biomarkers in unselected patients on admission to intensive or high-dependency care. Crit. Care 2013, 17, R60. [Google Scholar] [CrossRef]
  67. Schlapbach, L.J.; Graf, R.; Woerner, A.; Fontana, M.; Zimmermann-Baer, U.; Glauser, D.; Giannoni, E.; Roger, T.; Müller, C.; Nelle, M.; et al. Pancreatic stone protein as a novel marker for neonatal sepsis. Intensive Care Med. 2013, 39, 754–763. [Google Scholar] [CrossRef] [PubMed]
  68. Rass, A.A.; Talat, M.A.; Arafa, M.A.; El-Saadany, H.F.; Amin, E.K.; Abdelsalam, M.M.; Mansour, M.A.; Khalifa, N.A.; Kamel, L.M. The Role of Pancreatic Stone Protein in Diagnosis of Early Onset Neonatal Sepsis. Biomed. Res. Int. 2016, 2016, 1035856. [Google Scholar] [CrossRef]
  69. Dündar, M.A.; Ceran, E.; Akyildiz, B.N. Prognostic and diagnostic utility of pancreatic stone protein in pediatric sepsis and mortality. Turk. J. Med. Sci. 2024, 54, 744–751. [Google Scholar] [CrossRef]
  70. Wu, Q.; Nie, J.; Wu, F.X.; Zou, X.L.; Chen, F.Y. Prognostic value of high-sensitivity C-reactive protein, procalcitonin and pancreatic stone protein in pediatric sepsis. Med. Sci. Monit. 2017, 23, 1533–1539. [Google Scholar] [CrossRef]
  71. Bottari, G.; Caruso, M.; Paionni, E.; De Luca, M.; Romani, L.; Pisani, M.; Grandin, A.; Gargiullo, L.; Zampini, G.; Gagliardi, C.; et al. Accuracy of Pancreatic Stone Protein for diagnosis of sepsis in children admitted to pediatric intensive care or high-dependency care: A pilot study. Ital. J. Pediatr. 2023, 49, 134. [Google Scholar] [CrossRef]
  72. Gouel-Chéron, A.; Dupin, M.; Chanteperdix, M.; Chaillol, I.; Venet, F.; Pachot, A.; Monneret, G.; Floccard, B.; Allaouchiche, B. Concomitant assessment of PSP and NT-proCNP as predictive markers of sepsis in severe trauma patients under mechanical ventilation. Crit. Care 2013, 17, 434. [Google Scholar] [CrossRef]
  73. Filippidis, P.; Hovius, L.; Tissot, F.; Orasch, C.; Flückiger, U.; Siegemund, M.; Pagani, J.-L.; Eggimann, P.; Marchetti, O.; Lamoth, F. Serial monitoring of pancreatic stone protein for the detection of sepsis in intensive care unit patients with complicated abdominal surgery: A prospective, longitudinal cohort study. J. Crit. Care 2024, 82, 154772. [Google Scholar] [CrossRef] [PubMed]
  74. Prazak, J.; Irincheeva, I.; Llewelyn, M.J.; Stolz, D.; García de Guadiana Romualdo, L.; Graf, R.; Reding, T.; Klein, H.J.; Eggimann, P.; Que, Y.A. Accuracy of pancreatic stone protein for the diagnosis of infection in hospitalized adults: A systematic review and individual patient level meta-analysis. Crit. Care 2021, 25, 182. [Google Scholar] [CrossRef]
  75. Van Singer, M.; Brahier, T.; Brochu Vez, M.J.; Gerhard Donnet, H.; Hugli, O.; Boillat-Blanco, N. Pancreatic stone protein for early mortality prediction in COVID-19 patients. Crit. Care 2021, 25, 267. [Google Scholar] [CrossRef]
  76. Melegari, G.; Giuliani, E.; Di Pietro, G.; Alberti, F.; Campitiello, M.; Bertellini, E.; Rosa, A.; Pioda, A.; Battaglia, P.; Quarto, M.; et al. Point-of-care pancreatic stone protein measurement in critically ill COVID-19 patients. BMC Anesth. 2023, 23, 226. [Google Scholar] [CrossRef] [PubMed]
  77. Zuercher, P.; Moser, A.; Garcia de Guadiana-Romualdo, L.; Llewelyn, M.J.; Graf, R.; Reding, T.; Eggimann, P.; Que, Y.A.; Prazak, J. Discriminative performance of pancreatic stone protein in predicting ICU mortality and infection severity in adult patients with infection: A systematic review and individual patient level meta-analysis. Infection 2023, 51, 1797–1807. [Google Scholar] [CrossRef] [PubMed]
  78. Schneider, J.E.; Dick, K.; Cooper, J.T.; Chami, N. Pancreatic stone protein point-of-care testing can reduce healthcare expenditure in sepsis. Health Econ. Rev. 2022, 12, 39. [Google Scholar] [CrossRef]
  79. de Hond, T.A.P.; Oosterheert, J.J.; van Hemert-Glaubitz, S.J.M.; Musson, R.E.A.; Kaasjager, K.A.H. Pancreatic Stone Protein as a Biomarker for Sepsis at the Emergency Department of a Large Tertiary Hospital. Pathogens 2022, 11, 559. [Google Scholar] [CrossRef]
  80. Lee, G.H.; Kim, H.; Moon, H.W.; Yun, Y.M.; Park, M.; Lee, S.; Hur, M. Diagnostic and Prognostic Utilities of Pancreatic Stone Protein in Patients with Suspected Sepsis. Diagnostics 2024, 14, 2076. [Google Scholar] [CrossRef]
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Figure 1. PRISMA flow diagram.
Figure 1. PRISMA flow diagram.
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Figure 2. A schematic figure showing PSP metabolic pathway.
Figure 2. A schematic figure showing PSP metabolic pathway.
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Table 1. Summary of PSP levels across different populations and disease.
Table 1. Summary of PSP levels across different populations and disease.
ConditionPSP Levels (ng/ML)Notes
Healthy adults25.2–161.1 (mean 78.6; 95% range 15–142.2)Above 142.2 = high; below 15 = low
General population1–99.4 (median 9.2)No gender differences
ChildrenVery preterm newbornsMedian 2.6Age-dependent increase
Term newbornsMedian 6.3
Older childrenMedian 16.1
PregnancySingleton7.9 ± 2.6
Multiple9.17 ± 3.06Significantly higher than singleton
1st trimester6.94 ± 2.53Progressive rise with gestation
2nd trimester7.42 ± 2.21
3rd trimester8.33 ± 2.68
Neonatal sepsisSignificantly elevatedBetter negative predictive value
Sepsis167 (cutoff)Comparable or superior early prediction
Diabetes Type 2Elevated, correlates with HbA1cReflects chronic inflammation
Renal dysfunctionHigh due to reduced clearanceReflects renal impariment
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Vlahović Vlašić, N.; Zibar, L.; Smajić, P.; Švitek, L.; Drenjančević, D. Pancreatic Stone Protein: A Multifaceted Biomarker—A Comprehensive Review. Acta Microbiol. Hell. 2025, 70, 35. https://doi.org/10.3390/amh70030035

AMA Style

Vlahović Vlašić N, Zibar L, Smajić P, Švitek L, Drenjančević D. Pancreatic Stone Protein: A Multifaceted Biomarker—A Comprehensive Review. Acta Microbiologica Hellenica. 2025; 70(3):35. https://doi.org/10.3390/amh70030035

Chicago/Turabian Style

Vlahović Vlašić, Nika, Lada Zibar, Petra Smajić, Luka Švitek, and Domagoj Drenjančević. 2025. "Pancreatic Stone Protein: A Multifaceted Biomarker—A Comprehensive Review" Acta Microbiologica Hellenica 70, no. 3: 35. https://doi.org/10.3390/amh70030035

APA Style

Vlahović Vlašić, N., Zibar, L., Smajić, P., Švitek, L., & Drenjančević, D. (2025). Pancreatic Stone Protein: A Multifaceted Biomarker—A Comprehensive Review. Acta Microbiologica Hellenica, 70(3), 35. https://doi.org/10.3390/amh70030035

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