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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 June 2026 | Viewed by 13302

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Dr. Vija Lavinia

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Nuclear Medicine Department, Oncopole Claudius Regaud, 31059 Toulouse, France
Interests: endocrine oncology; theragnostics; molecular targeted radiotherapy; Lu-177 dotatate; Lu-177 PSMA; thyroid cancer; prostate cancer; neuroendocrine tumors
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Dear Colleagues,

As the clinical paradigm shifts from “treat what you see” to more refined de-escalation strategies, and with the increasing number of clinical trials related to the development of new radiopharmaceuticals for both diagnostic and therapeutic applications across various oncology fields, new challenges are emerging.

Improving patients’ quality of life and survival while minimizing serious side effects is paramount, especially in aging populations often burdened with complex treatment histories and long-standing disease. Therefore, clinicians are seeking either single or composite biomarkers that can help identify patients with aggressive disease, a high likelihood of rapid progression, or those prone to developing clinical events (prognostic biomarkers), as well as biomarkers that can predict a high probability of response to a given therapy (predictive biomarkers).

This Special Issue is dedicated to original work on the advances in molecular biology, imaging, and translational fields of research aiming at identifying or confirming different biomarkers related to molecular targeted radiotherapies.

Dr. Vija Lavinia
Guest Editor

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Keywords

biomarkers
molecular targeted radiotherapies
prognostic biomarkers
predictive biomarkers
single or composite biomarkers

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Published Papers (10 papers)

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Research

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11 pages, 802 KB

Open AccessArticle

The Role of Gasdermin B-Mediated Pyroptosis in Bladder Cancer Diagnosis

by Sara Pączek, Michał Olkowicz, Jacek Kudelski and Monika Gudowska-Sawczuk

Int. J. Mol. Sci. 2026, 27(8), 3540; https://doi.org/10.3390/ijms27083540 - 16 Apr 2026

Viewed by 257

Abstract

Bladder cancer (BC) is one of the most common urinary tract malignancies. In recent years, increasing attention has been paid to the role of pyroptosis—an inflammatory form of programmed cell death—in cancer development. Gasdermin B (GSDM B), a member of the gasdermin protein family, is involved in the regulation of inflammatory processes and the immune response, and its expression may be associated with cancer development and progression. The aim of the study was to assess GSDM B concentrations in the serum of patients with bladder cancer and to determine its potential diagnostic value in comparison with the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). This study included patients with bladder cancer hospitalized at the Department of Urology, Medical University of Białystok, and a healthy control group. GSDM B concentrations were determined by Enzyme-Linked Immunosorbent Assay (ELISA), while CEA and CA19-9 concentrations were determined by chemiluminescent microparticle immunoassay (CMIA). Concentrations in the serum of patients with bladder cancer were significantly higher than in the control group. A positive correlation was found between GSDM B and CEA and CA19-9 concentrations, as well as the age of the subjects. Receiver-operating characteristic (ROC) analysis demonstrated moderate but significant diagnostic value of GSDM B in differentiating patients with BC from healthy controls. No significant differences in GSDM B concentrations were observed between low- and high-grade tumors. These findings suggest that GSDM B may serve as a potential diagnostic marker for bladder cancer, particularly when used as part of a multimarker panel. Full article

(This article belongs to the Special Issue Molecular Biomarkers for Targeted Therapies)

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29 pages, 3286 KB

Open AccessArticle

Bioinformatic Approach to Identify Potential TGFB2-Dependent and Independent Prognostic Biomarkers for Ovarian Cancers Treated with Taxol

by Sanjive Qazi, Stephen Richardson, Mike Potts, Scott Myers, Saran Saund, Tapas De and Vuong Trieu

Int. J. Mol. Sci. 2025, 26(24), 11900; https://doi.org/10.3390/ijms262411900 - 10 Dec 2025

Viewed by 896

Abstract

High-grade serous ovarian carcinoma is the most common and aggressive form of ovarian cancer, accounting for over 60% of cases and nearly 75% of deaths, mainly due to late diagnosis and tumor aggressiveness. Standard treatment is platinum-based chemotherapy with paclitaxel, but relapse is frequent. This study aimed to identify prognostic biomarkers for patients with poor survival outcomes after Taxol treatment using bioinformatics analysis. We examined the effects of TGFB2 mRNA expression and other markers on overall survival in serous ovarian cancer using the TCGA database, applying a multivariate Cox model that included interaction terms to identify TGFB2-dependent and independent prognostic markers, and controlling for age and treatment type. Candidate TGFB2-independent prognostic markers from TCGA were further validated using patient data from the KMplotter database. High TGFB2 mRNA expression emerged as a prognostic biomarker for three potential gene targets (TRPV4, STAU2, and HOXC4) associated with improved OS at low levels of gene target expression, we identified four additional markers (CLIC3, ANPEP/LAP1, RIN2, and EMP1) that exhibited a TGFB2-independent negative correlation between mRNA expression and OS across the full spectrum of gene expression values in the ovarian cancer cohort validated using independent dataset from KMplotter, for Taxol-treated ovarian cancer patients. This study proposes a panel of potential prognostic biomarkers for the treatment of ovarian cancer patients, particularly by leveraging TGFB2-dependent mRNA expression as a significant biomarker, alongside four additional TGFB2-independent prognostic markers, for patients undergoing Taxol-based therapies. Future prospective clinical trials will be required to validate these prognostic markers. Full article

(This article belongs to the Special Issue Molecular Biomarkers for Targeted Therapies)

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15 pages, 2305 KB

Open AccessArticle

Reduced Activity of Soluble Fibroblast Activation Protein (sFAP) Represents a Biomarker of Aggressive Disease in Lymphoid Malignancies

by Jonas Klejs Hemmingsen, Marie Hairing Enemark, Anne Kathrine Nissen Pedersen, Emma Frasez Sørensen, Kristina Lystlund Lauridsen, Julie Bondgaard Løhde, Francesco d’Amore, Stephen Jacques Hamilton-Dutoit, Mette Bjerre and Maja Ludvigsen

Int. J. Mol. Sci. 2025, 26(23), 11248; https://doi.org/10.3390/ijms262311248 - 21 Nov 2025

Viewed by 732

Abstract

Fibroblast activation protein (FAP), a transmembrane serine protease expressed primarily in pathological conditions, plays a pivotal role in tumor progression. Despite extensive studies on FAP in solid tumors, its role in hematologic cancers, particularly lymphoid malignancies, remains underexplored. This study aimed to investigate the level and activity of soluble FAP (sFAP) in pre-therapeutic serum samples from 120 lymphoma patients. We measured sFAP serum levels using time-resolved immunofluorometric assay and sFAP activity with Förster resonance energy transfer assay. In addition, immunohistochemistry was used to analyze intratumoral FAP expression in tissue biopsies from a subset of B-cell lymphoma patients (n = 34). Notably, the results revealed significantly reduced circulating sFAP levels (p = 0.002) and activity (p < 0.001) in aggressive disease subtypes compared with indolent subtypes and healthy individuals. At the time of diagnosis, low sFAP activity correlated with inferior overall survival (both p < 0.001) in patients with the aggressive entities, suggesting altered FAP functionality in these tumors. Interestingly, measuring intratumoral FAP levels revealed an inverse pattern, with diffuse large B-cell lymphoma showing higher tissue FAP localization compared with follicular lymphoma (p < 0.001). These findings provide new insights into the biological and clinical significance of FAP in lymphoid malignancies, particularly highlighting the importance of sFAP activity as a potential prognostic marker in aggressive lymphoid malignancies. Full article

(This article belongs to the Special Issue Molecular Biomarkers for Targeted Therapies)

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12 pages, 1111 KB

Open AccessArticle

Metabolic Signatures in Lung Cancer: Prognostic Value of Acid–Base Disruptions and Serum Indices

by Florian Ponholzer, Marie-Christin Neuschmid, Helga Komi, Christina Bogensperger, Caecilia Ng, Herbert Maier, Paolo Lucciarini, Stefan Schneeberger and Florian Augustin

Int. J. Mol. Sci. 2025, 26(17), 8231; https://doi.org/10.3390/ijms26178231 - 25 Aug 2025

Cited by 3 | Viewed by 1441

Abstract

One characteristic of tumor cells is the increased anaerobic metabolism through glycolysis leading to an acidic environment of the tumor. This acidity is linked to tumor progression, invasion and metastasis, besides stimulated survival pathways in the malignant cells. The aim of our analysis is to investigate the role of systemic acid–base parameters such as the pH, bicarbonate, baseexcess and lactate in lung cancer patients. Furthermore, alterations in electrolytes and hemoglobin were investigated regarding their impact on overall survival. Data of 937 non-small-cell lung cancer (NSCLC) patients, who underwent anatomic video-assisted thoracoscopic surgery (VATS) resection, was collected in a prospectively maintained database and analyzed. To minimize confounding effects and due to the retrospective study design, we decided to use data from the first arterial blood gas analysis during surgery and the most recent lab results prior to surgery. We found significant correlations between low systemic bicarbonate (<20 mEq/L) and overall survival (p = 0.006). Hyponatremia (<135 mmol/L) correlated with lower 5-year overall survival (p = 0.004) and decreased disease-free survival (p = 0.017). Hypochloremia (<98 mmol/L) was linked to reduced overall survival (p = 0.003) and hypocalcemia (<1.15 mmol/L) with worse disease-free survival (p = 0.015). Hemoglobin under 12 g/dL for women and 13 g/dL for men was associated with poorer outcomes (p < 0.001). Other acid–base parameters such as the pH (p = 0.563), baseexcess (BE) (p = 0.290) and lactate (p = 0.527) did not show significant differences in overall or disease-free (pH: p = 0.130; BE: p = 0.148; lactate: p = 0.418) survival. Systemic bicarbonate, sodium, calcium, chloride and hemoglobin levels were found as prognostic markers and possible therapeutic targets to improve overall survival. Further investigations are necessary to develop therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Biomarkers for Targeted Therapies)

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Review

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18 pages, 1304 KB

Open AccessReview

Autophagy Modulation in Cancer Immunotherapy, Emerging Molecular Targets and Drug Selection Strategies

by Maroua Jalouli, Abdel Halim Harrath, Mohammed Al-Zharani and Md Ataur Rahman

Int. J. Mol. Sci. 2026, 27(5), 2183; https://doi.org/10.3390/ijms27052183 - 26 Feb 2026

Cited by 2 | Viewed by 932

Abstract

Cancer immunotherapy has revolutionized the treatment of cancer by harnessing the immune system to recognize and destroy malignant cells. However, a substantial proportion of patients exhibit primary or acquired resistance to these therapies, underscoring the urgent need to identify novel molecular targets to enhance therapeutic efficacy. Autophagy, an evolutionarily conserved cellular process of degradation and recycling, has emerged as a critical modulator of tumor immunity and the function of immune cells. In cancer cells, autophagy modulates antigen presentation, immunogenic cell death, metabolic reprogramming, and resistance to immune-mediated cell death. Concurrently, autophagy rigorously governs the viability, differentiation, and functional capacity of immune cells, including T cells, dendritic cells, macrophages, and natural killer (NK) cells. Dysfunctional autophagic flux in the tumor microenvironment can enhance immune evasion and limit the efficacy of immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccines. In this review, we provide an in-depth analysis of emerging molecular targets involved in the regulation of autophagy relevant to cancer immunotherapy. This includes key signaling pathways such as PI3K/AKT/mTOR, AMPK, Beclin-1 complexes, ULK1, and lysosomal regulators. Additionally, we explore the rational integration of the pharmacological modulation of autophagy, including small molecules, natural compounds, and nanoparticle-based drug delivery systems, with immunotherapeutic approaches. We highlight the importance of rational drug selection and combination therapies to overcome resistance to immunotherapy and minimize toxicity. Understanding the context-dependent role of autophagy will be essential for the development of next-generation, precision-targeted cancer immunotherapies. Therefore, a comprehensive understanding of the context-specific functions of autophagy in tumor and immune cells is crucial for devising precision-targeted combination methods that overcome immunotherapy resistance and produce more sustainable cancer treatment outcomes. Full article

(This article belongs to the Special Issue Molecular Biomarkers for Targeted Therapies)

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23 pages, 1177 KB

Open AccessReview

A Practical Roadmap for Clinical Translation of Metabolic Biomarkers: A Review

by Kyung-Hee Kim, Maro Yoo, Min Yeong Choi and Byong Chul Yoo

Int. J. Mol. Sci. 2026, 27(4), 2030; https://doi.org/10.3390/ijms27042030 - 21 Feb 2026

Cited by 1 | Viewed by 1906

Abstract

Metabolomics and lipidomics enable comprehensive profiling of metabolic states across diverse diseases and have generated a vast number of candidate biomarkers. Despite this progress, only a small fraction of metabolite-based biomarkers have achieved durable clinical translation. While this gap is often attributed to biological complexity or limited cohort size, increasing evidence suggests that failure more commonly reflects systematic misalignment between analytical measurement, biological interpretation, and clinical decision-making requirements. In this review, we argue that metabolites are not intrinsically unreliable biomarkers but are frequently overinterpreted as disease-specific indicators despite being highly context-dependent reporters of physiological state. We synthesize recurrent failure modes across the translational pipeline—including pre-analytical instability, ionization bias and semi-quantitative measurement, structural and annotation ambiguity, statistical overfitting, loss of disease specificity under systemic stress, and cohort-dependent performance collapse. Building on these insights, we propose a structured roadmap for the clinical translation of metabolite and lipid biomarkers. Rather than emphasizing further discovery, this framework prioritizes decision-oriented eligibility criteria encompassing pre-analytical robustness, analytical validity, molecular definition, biological interpretability, validation under real-world heterogeneity, and alignment with clinical utility and regulatory expectations. By reframing metabolic biomarkers as context-sensitive measurements embedded within clinical decision systems, this review provides practical guidance for investigators, clinicians, and regulators seeking to translate metabolomics and lipidomics into reliable tools for clinical practice. Full article

(This article belongs to the Special Issue Molecular Biomarkers for Targeted Therapies)

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16 pages, 317 KB

Open AccessReview

Artificial Intelligence-Driven Integration of ECG and Molecular Biomarkers in Pulmonary Embolism

by Bojana Uzelac and Sanja Stanković

Int. J. Mol. Sci. 2026, 27(2), 813; https://doi.org/10.3390/ijms27020813 - 14 Jan 2026

Viewed by 835

Abstract

Pulmonary embolism (PE) is a serious cardiovascular condition and the third leading cause of cardiovascular mortality worldwide. However, its clinical presentation is often non-specific, making timely detection challenging. Biomarkers are commonly used to support early diagnosis and risk stratification. Molecular biomarkers provide information related to coagulation, inflammation, and cardiac injury. Electrocardiography (ECG) reflects cardiac functional changes caused by right ventricular (RV) stress and dilation secondary to increased pulmonary vascular resistance. Individually, these biomarkers have limited diagnostic accuracy. A promising approach to improving PE management involves integrating multimodal clinical data using Artificial Intelligence (AI). AI-based models can detect subtle patterns in ECG signals and molecular biomarker profiles that may be missed by conventional analysis. Combining these data sources may enhance diagnostic accuracy, refine risk assessment, and support personalized treatment. Despite ongoing challenges, including data quality, interpretability, and ethical considerations, AI-driven integration of ECG and molecular biomarkers represents a significant step forward in PE diagnosis and management. Further validation in large, prospective clinical studies is required. Full article

(This article belongs to the Special Issue Molecular Biomarkers for Targeted Therapies)

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20 pages, 1723 KB

Open AccessReview

Phosphatidylserine Externalization in Cancer: Biology, Immune Suppression, and Emerging Theragnostic Strategies

by Maro Yoo and Kyung-Hee Kim

Int. J. Mol. Sci. 2026, 27(2), 697; https://doi.org/10.3390/ijms27020697 - 9 Jan 2026

Viewed by 1191

Abstract

Phosphatidylserine (PS) externalization is a conserved membrane stress signal that becomes chronically dysregulated in cancer cells and tumor-associated endothelium. In vivo, PS does not exist as a free lipid signal but is presented in specific membrane-associated forms, including apoptotic or stressed cell surfaces, PS-rich extracellular vesicles, and circulating lipid particles. Unlike apoptosis-associated transient PS exposure, malignant PS externalization arises from metabolic rewiring, oxidative stress, epigenetic silencing of flippases, and microenvironmental cues, creating an immunosuppressive interface across the tumor–host boundary. This review synthesizes mechanistic, immunological, and clinical evidence on PS biology, including its roles in tumor immune evasion, extracellular vesicle-mediated systemic suppression, and vascular remodeling. We further summarize the development and evaluation of PS-targeted therapeutic platforms—such as bavituximab, SapC-DOPS/BXQ-350, and PS-directed imaging agents—and highlight their translational potential in combination with radiotherapy, chemotherapy, and checkpoint inhibitors. Chronic PS externalization, as manifested through distinct cellular and vesicular carriers, represents a unifying biomarker of tumor stress, immune suppression, and therapeutic vulnerability, offering a next-generation axis for theragnostic cancer management. Full article

(This article belongs to the Special Issue Molecular Biomarkers for Targeted Therapies)

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23 pages, 2776 KB

Open AccessReview

Uric Acid in Cerebral Ischemia: A Systematic Review of Its Biomarker Value and Role in Neuroprotection

by Iulian Roman-Filip, Corina Roman-Filip, Valentin Morosanu, Sebastian Andone, Zoltan Bajko and Rodica Balasa

Int. J. Mol. Sci. 2025, 26(21), 10268; https://doi.org/10.3390/ijms262110268 - 22 Oct 2025

Cited by 3 | Viewed by 2019

Abstract

Uric acid (UA), the end product of purine metabolism, exhibits dual roles in cerebral ischemia—it functions as a cerebroprotective antioxidant in acute settings and as a pro-oxidant contributor to vascular damage in chronic conditions. Some studies suggest that higher UA levels may confer protection during the acute phase of stroke, particularly in subgroups such as women, hyperglycemic patients, and thrombectomy recipients. In contrast, chronic hyperuricemia has been consistently linked to adverse cardiovascular outcomes, increased stroke recurrence, and poor recovery. A systematic review was conducted in accordance with PRISMA 2020 guidelines. MEDLINE, Google Scholar, and the Cochrane Library were searched up to April 2025. Eligible studies included adults with acute ischemic stroke in whom UA levels were reported within 72 h of onset. Primary outcomes were mortality, functional outcome (mRS), and neurological deterioration. Thirty-five studies involving over 15,000 patients were included. Evidence regarding UA’s prognostic value was heterogeneous. Approximately 80% of studies identified high UA levels as being associated with increased mortality, stroke recurrence, or disability. However, randomized trials—notably the URICO-ICTUS trial—suggested short-term neuroprotective effects in specific subgroups. Several studies also reported U- or J-shaped relationships, indicating that both low and high UA levels may adversely affect outcomes. Uric acid demonstrates a paradoxical role in cerebral ischemia. Acute-phase antioxidant effects may offer therapeutic potential, whereas chronic hyperuricemia is more often associated with vascular injury and worse long-term outcomes. UA may serve as a useful biomarker when incorporated into multifactorial prognostic models, but further well-controlled studies are needed to clarify its clinical utility in stroke prognosis and treatment. Full article

(This article belongs to the Special Issue Molecular Biomarkers for Targeted Therapies)

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14 pages, 633 KB

Open AccessReview

A Systematic Review on Biomarkers for Gestational Diabetes Mellitus Detection in Pregnancies Conceived Using Assisted Reproductive Technology: Current Trends and Future Directions

by Angeliki Gerede, Efthymios Oikonomou, Anastasios Potiris, Christos Chatzakis, Peter Drakakis, Ekaterini Domali, Nikolaos Nikolettos and Sofoklis Stavros

Int. J. Mol. Sci. 2025, 26(17), 8234; https://doi.org/10.3390/ijms26178234 - 25 Aug 2025

Cited by 2 | Viewed by 2528

Abstract

Gestational diabetes mellitus (GDM) is a frequently encountered medical complication during pregnancy that is increasing at a rapid pace globally, posing significant public health concerns. Similarly, there is a rising trend in the number of women who have utilized assisted reproductive technology (ART). Numerous studies have been carried out to investigate the relationship between GDM and ART. This comprehensive systematic review seeks to identify potential biomarkers for the early diagnosis of GDM in pregnancies conceived through ART. We conducted a PubMed search covering the past five years to identify studies that explore biomarkers associated with the development of GDM in pregnancies conceived through ART. The outcome measures included human chorionic gonadotropin (HCG), the body mass index (BMI), the Follicle Stimulating Hormone to Luteinizing Hormone (FSH/LH) ratio, increased hemoglobin A1c levels, fasting insulin concentrations, homeostatic model assessment of insulin resistance (HOMA-IR), triglyceride levels, total cholesterol levels, low-density lipoprotein cholesterol concentrations, low-density lipoprotein/high-density lipoprotein (LDL/HDL), total cholesterol to high-density lipoprotein (TC/HDL), the estradiol/follicle ratio, soluble fms-like tyrosine kinase-1 (sFlt-1), Placental Growth Factor (PLGF), endometrial thickness, and psychological stress. Seventeen studies were included. The identification and development of serum or ultrasound biomarkers for the early detection of GDM in pregnancies conceived through ART pose considerable challenges. These challenges arise from the multifactorial nature of GDM, the methodological variations in ART, and the limited availability of relevant studies. The most promising biomarker identified was the estradiol/follicle ratio. Women with a higher estradiol/follicle ratio exhibited significantly lower rates of GDM. There is a pressing necessity for biomarkers to enable the early detection of GDM in pregnancies conceived through ART. E2 levels, β-hCG, and the E2/F ratio, along with the TC/HDL and LDL/HDL ratios, show potential as reliable biomarkers for identifying GDM. Full article

(This article belongs to the Special Issue Molecular Biomarkers for Targeted Therapies)

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