From Tumor Marker to Congestion Indicator: The Expanding Role of CA-125 in Heart Failure and Beyond.

CA125 has recently been identified as a multifaceted biomarker in both acute and chronic heart failure (HF). It serves a dual role: first, as a diagnostic tool that provides a ‘real‐time' snapshot of current systemic congestion; and second, as a powerful prognostic indicator for long‐term monitoring. While a threshold of 35 U/mL helps identify patients at high risk for adverse outcomes, serial measurements allow clinicians to monitor the efficacy of decongestion therapy over time. High CA125 levels correlate with worse longitudinal outcomes, including increased hospitalization rates and mortality, often providing predictive power that complements traditional markers like NT‐proBNP. In these conditions, CA125 elevation can be interpreted as a sign of congestion, stasis and organ congestion due to fluid overload as a result of poor cardiac performance [ 5 , 11 ]. CA125 is released from mesothelial cells upon both mechanical stress, inflammation, and fluid overload, making it a highly sensitive marker for congestion [ 37 ]. CA125 levels correlate with clinical signs of congestion like pulmonary edema, pleural effusion, and peripheral edema and may be elevated in acute decompensated HF [ 38 ]. In chronic HF, elevated CA125 levels reflected residual congestion and inadequate HF management [ 39 ]. Apart from its utility as a diagnostic marker, CA125 shows prognostic value in HF. High CA125 levels correlate with worse outcomes, including increased hospitalization rates, higher mortality, and poorer quality of life [ 40 ]. Its predictive powers for rehospitalization and death are equal to or better than those of traditional biomarkers like NT‐proBNP [ 41 ]. CA125 also assists in risk stratification, informing clinicians about high‐risk patients who may be amenable to aggressive treatment [ 2 ]. CA125 has received increasing interest as a marker of congestion in renal failure, especially among patients with chronic kidney disease (CKD) and end‐stage renal disease (ESRD) [ 42 ]. Fluid overload in renal failure can attribute to increased CA125 from the reduced renal excretion of sodium and water [ 43 ]. Existing studies have indicated that CA125 levels reflect clinical features of volume overload, such as edema, ascites, and pleural effusion; thus, CA125 is a suitable biomarker for congestion in renal failure [ 44 ]. Moreover, in hemodialysis patients with less effective removal of extracellular water, the high concentrations of CA125 reflect a chronic state of volume overload [ 45 ]. Aside from being a diagnostic, CA125 also has prognostic value in renal failure. High CA125 is an independent risk factor for hospitalization, cardiovascular events, and death in patients with CKD and ESRD [ 46 ]. It has been shown to be a marker of chronic inflammation and volume overload, both of which are poor prognostic markers, and it is thought to gain most of its utility in predicting adverse outcomes from these mechanisms [ 47 ]. Thus, CA125 is an essential determinant of congestion, which facilitates risk stratification in renal failure for the achievement of optimal fluid control and patient‐oriented outcomes [ 44 ]. CA125 has also been shown to be a marker of congestion in liver disease and cirrhosis, especially in the setting of fluid overload and portal hypertension. In cirrhosis, due to the elevation of portal pressure and systemic inflammation, there is retention of liquids in the peritoneal cavity (ascites) and other serous membranes, promoting increased release of CA125 from activated mesothelial cells [ 3 ]. In patients with ascites due to liver cirrhosis, increased CA125 levels are often detected, correlating with the severity of the fluid retention and congestion [ 48 ]. Even though the values of CA125 correlate with the grade of ascites, but also with other complications of cirrhosis (for instance hepatic hydrothorax) [ 49 ]. Furthermore, elevated levels of CA125 are also correlated with the progression of liver disease; CA125 levels are significantly higher in patients with decompensated cirrhosis compared to those with compensated disease [ 50 ]. Moreover, CA125 serves a prognostic role in patients with liver disease beyond its diagnostic utility. Increased levels correlate with higher likelihoods of complications, hospitalization, and death because they reflect the degree of congestion and systemic inflammation [ 10 ]. CA125 has also been explored as a marker of congestion in conditions beyond heart failure, renal failure, and liver disease. In pulmonary hypertension, elevated CA125 levels correlate with right ventricular dysfunction and fluid retention, reflecting the severity of congestion [ 8 ]. Similarly, in pulmonary edema due to acute respiratory distress syndrome (ARDS) or other causes, CA125 levels rise in response to fluid accumulation in the pleural and pericardial spaces [ 51 ]. Additionally, CA125 has been studied in systemic inflammatory conditions like sepsis, where fluid overload and capillary leakage contribute to its elevation [ 52 ]. Carbohydrate antigen‐125 (CA‐125) is a glycoprotein originated from the epithelial serous cells, widely known for its implication in screening, diagnosing, and monitoring ovarian cancer. Although initially established as an oncological marker, high levels of CA‐125 have been observed in other diseases such as heart failure, liver cirrhosis, and pelvic inflammatory diseases [ 13 , 53 , 54 ]. CA‐125 is produced by mesothelial cells in response to serosal fluid accumulation or inflammatory stimuli, which may explain its elevation in patients with pericardial, pleural, or peritoneal effusions [ 55 , 56 , 57 ]. Recent studies have demonstrated that CA‐125 levels show strong correlations with hemodynamic parameters—such as right atrial pressure and pulmonary capillary wedge pressure—as well as with clinical signs of systemic congestion, including increased inferior vena cava (IVC) diameter, pleural effusion, and peripheral edema [ 40 , 58 ]. CA125 has been consistently shown to be associated with fluid overload across a range of malignant and non‐malignant conditions. For instance, elevated serum CA125 levels have been linked to the volume of pleural effusion in individuals with chronic obstructive pulmonary disease, and similarly with the buildup of serosal fluids and ascites in patients suffering from ovarian cancer and various other benign or malignant disorders [ 59 , 60 ]. Supporting this notion, among patients with cirrhosis, serum CA‐125 levels are seven times higher in those with ascites compared to those without, and show a strong correlation with ascitic fluid volume [ 10 ]. Similarly, individuals with tuberculous pleurisy exhibit more than twice the CA‐125 levels seen in pulmonary TB, with levels declining as pleural fluid decreases following anti‐tuberculosis treatment [ 61 ]. These observations suggest that CA‐125 may serve as a valuable biomarker for the assessment and management of overall body congestion in various clinical settings. While traditional biomarkers like NT‐proBNP reflect myocardial stretch, CA125 provides a distinct “extravascular” perspective by quantifying the impact of that stretch on the serous membranes. Comparative studies demonstrate that CA125 exhibits diagnostic performance comparable to NT‐proBNP for detecting fluid overload. In chronic heart failure management, a cutoff value of 33.3 U/mL provides strong specificity (85%). Critically, while its diagnostic value is used to trigger diuretic adjustment, its prognostic value remains robust even after clinical symptoms of congestion have resolved, suggesting it captures subclinical or “residual” congestion that traditional physical exams might miss [ 62 , 63 ]. The diagnostic value of CA‐125 has been established by numerous clinical investigations demonstrating its elevation during acute heart failure episodes, where it serves as a reliable indicator of underlying fluid accumulation and elevated venous pressures throughout the body. In a narrative review by Marianescu et al, in 2024, a CA 125 level of 35 U/mL has been suggested as a threshold to identify patients at low risk of adverse outcomes after admission for acute heart failure. Levels above this cutoff indicate a higher risk and could help guide more aggressive decongestion treatment, including increased doses of loop diuretics, which significantly enhance clinical confidence when evaluating and categorizing a patient's congestive status. CA125, as a biomarker, provides valuable complementary information alongside traditional clinical assessment methods [ 5 ]. Additionally, CA‐125 has shown a significant predictive capacity for risk stratification, particularly in high‐risk scenarios such as transcatheter aortic valve implantation (TAVI), where its levels may help identify patients susceptible to adverse outcomes [ 64 ]. Comparative studies demonstrate that CA125 exhibits diagnostic performance comparable to NT‐proBNP for detecting fluid overload. In chronic heart failure management, a cutoff value of 33.3 U/mL provides strong specificity (85%), making it useful for confirming fluid congestion. Conversely, when screening for general fluid overload across various clinical scenarios, a lower threshold of 16 U/mL yields higher sensitivity (86%), allowing for better detection of potential cases that warrant further evaluation [ 62 ]. Moreover, in a cross‐sectional study by Falcao et al., CA125 presented behavior similar to NT‐proBNP in patients with ST‐elevation myocardial infarction (STEMI), with a diagnostic threshold of 12.45 U/mL for detecting pulmonary congestion in this specific patient population [ 51 ]. These context‐specific cutoff values highlight the importance of clinician judgment when interpreting CA125 results and integrating them into comprehensive patient assessment protocols. Utilizing CA‐125 in conjunction with BNP may improve the precision of risk assessment in individuals experiencing heart failure episodes [ 63 ]. Notably, CA125 serves as a prognostic indicator, with research demonstrating a correlation between elevated levels and increased risks of all‐cause mortality and hospital readmissions in heart failure patients [ 65 , 66 ]. Elevated levels of CA‐125 demonstrate a significant association with heart failure progression, exhibiting correlations with established clinical parameters, including New York Heart Association (NYHA) functional classification and echocardiographic findings of fluid accumulation such as effusions and edema [ 67 ]. This relationship suggests CA‐125 serves a dual role beyond mere diagnosis, offering valuable prognostic information regarding disease severity and potentially enabling more precise stratification of cardiac decompensation states. CA125 has also emerged as a potential tool for guiding therapeutic decisions. Recent evidence indicates that CA125‐guided treatment strategies can lead to improved outcomes, including decreased hospitalization for heart failure and reduced all‐cause mortality, compared to standard approaches [ 68 , 69 ]. Incorporating CA‐125 monitoring into routine care could enhance the regulation of diuretic therapy after acute heart failure episodes, ultimately improving patient management and healthcare resource efficiency [ 70 ]. Despite its advantages, CA‐125 demonstrates several limitations and challenges as a biomarker; one of the primary concerns is false positive and false negative results. CA‐125 levels can be within the normal range even in patients with cancer, which constitutes a false negative. However, it can arise from benign conditions such as endometriosis or pelvic inflammatory disease. This variability can complicate clinical decision‐making and may lead to delayed or incorrect diagnoses [ 71 , 72 ]. Although numerous studies have proposed CA‐125 as a potential prognostic biomarker in heart failure and other conditions, its association with outcomes varies among diverse patient populations and disease contexts. The prognostic utility of CA‐125 is further challenged by individual variability, as its level interpretation may be substantially affected by patient‐specific characteristics [ 40 , 73 , 74 ] (Table  1 ). Clinical utility of CA‐125 across different disease states. Elevated CA‐125 correlates with right‐sided volume overload, jugular venous distension, ascites, and pleural effusions. Indicates residual congestion in chronic HF. Associated with mechanical stress, inflammation, and fluid overload. Elevated CA‐125 correlates with right‐sided volume overload, jugular venous distension, ascites, and pleural effusions. Indicates residual congestion in chronic HF. Associated with mechanical stress, inflammation, and fluid overload. Cutoff of 35 U/mL for risk stratification in acute HF. Cutoff of 35 U/mL for risk stratification in acute HF. Correlates with NT‐proBNP and congestion markers (edema, effusions). Correlates with NT‐proBNP and congestion markers (edema, effusions). Predicts worse outcomes (hospitalization, mortality). Comparable or superior to NT‐proBNP in risk prediction. Predicts worse outcomes (hospitalization, mortality). Comparable or superior to NT‐proBNP in risk prediction. Reflects fluid overload (edema, ascites, pleural effusion). Elevated in hemodialysis patients due to chronic volume overload. Reflects fluid overload (edema, ascites, pleural effusion). Elevated in hemodialysis patients due to chronic volume overload. Useful for detecting volume overload in CKD/ESRD. Useful for detecting volume overload in CKD/ESRD. Independent predictor of cardiovascular events, hospitalization, and death. Independent predictor of cardiovascular events, hospitalization, and death. Linked to chronic inflammation and fluid retention. Linked to chronic inflammation and fluid retention. Correlates with ascites severity and portal hypertension. Higher in decompensated versus compensated cirrhosis. Correlates with ascites severity and portal hypertension. Higher in decompensated versus compensated cirrhosis. Strong association with ascitic fluid volume. Strong association with ascitic fluid volume. Useful in hepatic hydrothorax. Useful in hepatic hydrothorax. Predicts disease progression, complications, and mortality. Predicts disease progression, complications, and mortality. Elevated in right ventricular dysfunction and pleural/pericardial effusions. Rises in ARDS, sepsis, and pulmonary edema. Elevated in right ventricular dysfunction and pleural/pericardial effusions. Rises in ARDS, sepsis, and pulmonary edema. Correlates with fluid retention in pulmonary hypertension. Correlates with fluid retention in pulmonary hypertension. Declines with decongestion (e.g., post‐TB treatment). Declines with decongestion (e.g., post‐TB treatment). May predict adverse outcomes in TAVI and other high‐risk scenarios. May predict adverse outcomes in TAVI and other high‐risk scenarios. Released from mesothelial cells due to mechanical stress/inflammation. ‐ Associated with VEGF, TNF‐α, IL‐1β, IL‐6. Released from mesothelial cells due to mechanical stress/inflammation. ‐ Associated with VEGF, TNF‐α, IL‐1β, IL‐6. Cutoffs: 16 U/mL (high sensitivity for screening). 33.3 U/mL (high specificity for HF). Cutoffs: 16 U/mL (high sensitivity for screening). 33.3 U/mL (high specificity for HF). 12.45 U/mL (STEMI with pulmonary congestion). 12.45 U/mL (STEMI with pulmonary congestion). Guides diuretic therapy and decongestion strategies. Guides diuretic therapy and decongestion strategies. Combined with NT‐proBNP/CRP improves risk stratification. Combined with NT‐proBNP/CRP improves risk stratification. False positives: Benign conditions (endometriosis, PID). False negatives: Normal levels despite congestion/cancer. Non‐specific; requires clinical context. False positives: Benign conditions (endometriosis, PID). False negatives: Normal levels despite congestion/cancer. Non‐specific; requires clinical context. Needs validation in diverse populations. Needs validation in diverse populations. Lacks standardized cutoffs for non‐HF conditions. Lacks standardized cutoffs for non‐HF conditions. Prognostic value varies by patient‐specific factors. Prognostic value varies by patient‐specific factors. Potential therapeutic target (anti‐CA‐125 immunotherapy). Role in guiding decongestive therapy. Potential therapeutic target (anti‐CA‐125 immunotherapy). Role in guiding decongestive therapy. Integration into multimodal biomarker panels (NT‐proBNP, CRP). Integration into multimodal biomarker panels (NT‐proBNP, CRP). Large‐scale trials needed for cutoff validation and outcome prediction. Large‐scale trials needed for cutoff validation and outcome prediction. There is increasing interest in the role of CA‐125 as a potential therapeutic target. In the oncology field, particularly ovarian cancer, there have been clinical trials regarding anti‐CA‐125 immunotherapy [ 75 ], however, its use in in nonmalignant conditions characterized by fluid retention and systemic inflammation is still unveiled. Given that CA‐125 is secreted by mesothelial cells in response to serosal irritation, it may have clinical utility in guiding treatment decisions and earlier diagnosis in conditions such as heart failure, liver cirrhosis, nephrotic syndrome, peritoneal tuberculosis and also endometriosis. Several studies have demonstrated a correlation between elevated CA‐125 levels and the degree of volume overload, as well as the patient's response to diuretic therapy, highlighting its promise as a tool for monitoring therapeutic response and guiding fluid management strategies. In addition to its established role as a tumor marker in oncology, CA‐125 has shown promising complementary information when combined with other markers such as N‐terminal pro–B‐type natriuretic peptide (NT‐proBNP) and C‐reactive protein (CRP), in reflecting mesothelial stress, cardiac strain, and systemic inflammation. So, it is worth being integrated into multimodal biomarker panels of non‐malignant fluid‐overload syndromes, aimed at improving diagnostic accuracy and treatment individualization. Ultimately, to fully validate the role of CA‐125 in the management of congestive states, large‐scale prospective trials are warranted. These should aim to establish clinically relevant cutoff values, assess serial changes in CA‐125 in response to therapy, and evaluate its predictive value for hospitalization, morbidity, and mortality.

Minoo Heidari Almasi and Amirahmad Nassiri: conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. Seyed Amirhossein Salehi and Azin Ebrahimi: Designed the data collection instruments, collected data, carried out the initial analyses, and reviewed and revised the manuscript. Ladan Heidaresfahani Coordinated and supervised data collection and critically reviewed the manuscript for important intellectual content. All authors have read and approved the final version of the manuscript. Minoo Heidari Almasi had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

The authors received no specific funding for this work.

A comprehensive literature review was conducted to explore the role of CA‐125 as a biomarker of systemic congestion and fluid overload. The search strategy aimed to identify relevant studies published in English from 1984 to 2025, focusing on its diagnostic and prognostic utility in populations with heart failure, renal failure, liver disease, pulmonary hypertension, and other conditions. We employed databases including PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. Keywords and phrases used during the search included “CA‐125,” “carbohydrate antigen 125,” “MUC16,” “systemic congestion,” “fluid overload,” “heart failure,” “renal failure,” “liver disease,” “pulmonary hypertension,” “diagnostic criteria,” and “prognostic value.” Boolean operators (“AND,” “OR”) were used to refine the search strategy. For example, the search string combined terms such as (“CA‐125” OR “carbohydrate antigen 125”) AND (“systemic congestion” OR “fluid overload”) AND (“heart failure” OR “renal failure” OR “liver disease”). Studies were included if they described aspects relevant to the definition, diagnostic criteria, or disease‐specific context of CA‐125 in systemic congestion. The review emphasized clinical trials, meta‐analyses, systematic reviews, observational studies, and narrative reviews. Studies providing insights into the pathophysiological mechanisms of CA‐125 production, particularly in response to mechanical stress, inflammation, and endothelial dysfunction, were also included. Articles not reported in English or deemed irrelevant to the research question were excluded. Three independent researchers (S.A.S., A.E., and L.H.E.) reviewed the titles and abstracts of the identified studies to select eligible articles. Full‐text reviews were conducted for studies meeting the inclusion criteria. Discrepancies between reviewers were resolved through discussion, and a third reviewer (M.H.A) was consulted when consensus could not be reached.

A total of 2256 studies were identified through database searches. After removing duplicates and screening titles and abstracts, 421 studies were selected for full‐text review. Of these, 76 studies met the inclusion criteria and were included in the review. The selection process is summarized in a PRISMA flow diagram (Figure  1 ). Prisma flowchart illustrating the process of screening. CA‐125, a high‐molecular‐weight glycoprotein, was first identified in 1981 and is encoded by the MUC16 gene. Initially recognized as a tumor marker, it is now understood to be a pro‐inflammatory molecule with physiological functions as a transmembrane mucin. CA‐125 is expressed in various epithelial tissues and mesothelial surfaces, including those lining the serosal cavities such as the peritoneum, pleura, and pericardium. Beyond its oncological significance, CA‐125 has been detected in non‐malignant conditions, including cirrhosis, tuberculosis, peritonitis, and post‐abdominal surgeries, further supporting its role in inflammation and serosal immune responses [ 13 , 14 , 15 ]. The synthesis of CA‐125 in congestive states is driven by the MMT. When venous congestion occurs, the resulting mechanical stress on serosal surfaces triggers the JNK signaling pathway. This results in the release of the CA‐125 glycoprotein into the peripheral circulation. Mesothelial cells, which line the serosal cavities, play a crucial role in maintaining the integrity and homeostasis of serous membranes [ 16 ]. Beyond their structural role, these cells contribute to inflammation management and tissue homeostasis. A fundamental mechanism underlying their function is the epithelial‐to‐mesenchymal transition [ 16 ], a process involved in embryogenesis, inflammation, tumorigenesis, and fibrosis. Within the broader context of EMT, a specific variation known as MMT occurs, wherein mesothelial cells transform into a mesenchymal‐like phenotype. During MMT, mesothelial cells can differentiate into fibroblast‐like or macrophage‐like cells, allowing them to produce and release cytokines and inflammatory mediators, thus modulating both local and systemic immune responses. mesothelial cells modulate inflammatory cascades by presenting antigens to T cells and releasing bioactive molecules, including cytokines, growth factors, extracellular matrix (ECM) components, and proteases. Through these dynamic interactions, they play a crucial role in both the initiation and resolution of inflammation, as well as in tissue repair and fibrosis regulation. Given their multifaceted functions, mesothelial cells represent potential therapeutic targets in inflammatory and fibrotic disorders [ 17 , 18 , 19 , 20 , 21 , 22 ]. Concurrently, we observe endothelial‐to‐mesenchymal transition (EndMT), in which the endothelium, a specialized subtype of epithelial tissue, undergoes a transition to a mesenchymal phenotype. Moreover, endothelial dysfunction is not only addressed to vasodilation but also a proinflammatory condition [ 13 , 23 , 24 ]. This phenomenon allows for the extension of our understanding of EMT to include endothelial cells, thereby providing insight into the underlying mechanisms of cardiovascular diseases and related processes [ 25 ]. Peripheral venous congestion causes the release of inflammatory mediators, neurohormones, and activation of endothelial cells [ 16 ]. Notably, it has been established that venous congestion changes expression patterns in the endothelial cells towards the activated state, leading to upregulation of pro‐oxidant, proinflammatory and vasoconstricting factors [ 26 ]. Fluid overload functions as a mechanical stressor to the aforementioned surfaces, even after cessation of fluid streaming [ 27 , 28 ]. Mechanical stress and inflammatory stimuli induced by fluid shear stress are transduced to the cytoplasm through c‐JNK signaling pathways [ 29 ]. This signaling pathway, first characterized as a stress‐activated member of the MAPK family, is now recognized for its diverse functions, many of which remain under investigation [ 30 ]. JNK activation promotes CA‐125 synthesis and secretion; mechanical stress‐induced alterations in cell morphology and membrane stability trigger the activation of the O‐glycosylated extracellular domain of CA‐125, resulting in its shedding from mesothelial cells and subsequent elevation in peripheral concentration [ 4 , 29 , 31 ]. It can be concluded that the mechanical stress induced by excessive fluid accumulation acts as the intermediary between volume overload and the elevated concentrations of CA‐125. Conversely, a deeper investigation into the pathophysiology of EMT has identified JNK as a crucial regulator of TGF‐β‐induced EMT [ 32 , 33 ], highlighting cJNK as a central mediator that connects mechanical stress, EMT, and the elevation of CA‐125. The reliability of CA125 as a marker of serosal involvement is supported by a parallel body of evidence in non‐malignant serous effusions. Studies in tuberculous pleurisy and connective tissue diseases demonstrate that CA125 levels correlate with the presence and volume of effusions across diverse etiologies. This reinforces the interpretation of elevated CA125 as a universal signal of mesothelial irritation, whether triggered by infection, autoimmunity, or, as explored here, hemodynamic congestion. Evidence suggests a positive correlation between CA‐125 and VEGF, TNF‐α, and IL‐1 [ 34 ]. Additionally, the proinflammatory cytokines TNF‐α and IFN‐γ have been shown to stimulate MUC16 gene expression across various cellular contexts [ 35 ]. Furthermore, an interdependent relationship has been demonstrated between CA‐125 levels and NT‐proBNP, IL‐6, and IL‐1β in the coronary sinus of patients with congestive heart failure [ 36 ]. Notably, IL‐1β has been identified as the most potent stimulus for apical CA‐125 secretion [ 13 ].

CA‐125, a high‐molecular‐weight glycoprotein encoded by the MUC16 gene, has long been established as a tumor marker for epithelial ovarian cancer [ 1 ]. However, growing evidence highlights its role beyond oncology, particularly in conditions characterized by systemic congestion and fluid overload. Elevated CA‐125 levels are frequently observed in HF, hepatic congestion, renal diseases, and other disorders associated with extracellular volume expansion, suggesting its potential as a biomarker of hemodynamic stress and tissue congestion [ 2 , 3 , 4 ]. The link between CA‐125 and congestion was originally recorded in HF patients manifesting right‐sided volume overload [ 5 ], in whom CA‐125 levels correlated with jugular venous distension, ascites, and pleural effusions [ 6 , 7 ]. This association was later extended to pulmonary hypertension [ 8 ], constrictive pericarditis [ 9 ], and hepatic congestion [ 10 ], with common pathways of fluid‐driven inflammation and consequent endothelial dysfunction suggested as contributing factors [ 11 ]. Elevated CA‐125 levels often remain elevated after acute decongestion, suggesting that its action may not be simply fluid status, but it may play a role in longer processes such as fibrosis and remodeling [ 12 ]. This review article intends to provide a comprehensive overview of the relationship between CA‐125 and systemic congestion. While CA‐125 is a well‐known biomarker for ovarian cancer, new data relating to this antigen suggest that it also indicates mesothelial activation due to congestion, inflammation and hemodynamic stress. We will discuss the pathophysiological pathways connecting CA‐125 to fluid overload, including a novel mechanism, mediated by the synthesis of CA‐125 from serosal membranes in response to increased venous pressures. We will also evaluate clinical studies showing a relationship with congestion markers (e.g., jugular venous pressure, edema) and prognostic value for HF exacerbation and mortality. Beyond cardiology, we will explore CA‐125 elevations in conditions related to hepatic, renal, and pulmonary congestion. We will lastly cover existing limitations, including non‐specificity and confounding factors, and propose future research avenues and the potential utility of such an approach in guiding decongestive therapies. This review article provides a comprehensive overview of the relationship between CA125 and systemic congestion. While CA125 is primarily known as an oncologic marker for ovarian cancer, the scope of this review is focused specifically on its emerging role in non‐malignant conditions. New data suggest that CA125 serves as a dynamic indicator of mesothelial activation due to congestion, inflammation, and hemodynamic stress.

The lead author Amirahmad Nassiri affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

The authors declare no conflicts of interest.