Open research questions in GDF15 and Related Biomarkers

What the literature leaves open

• Fourth, since skeletal muscle is not the source of the rise in plasma GDF15 during vigorous submaximal exercise, the responsible organ(s) as well as the mech- anisms remain to be identified in humans. In addition, the role of skeletal muscle as a potential source of GDF15 has not been previously assessed in humans.

  Circulating levels of growth differentiation factor-15 and its genetic variants -3148C>G (rs4808793) in pediatric cardiac patients · 2026 · DOI

• The incorporation of SYCN could potentially improve the selection of individuals requiring further diagnostic evaluation, such as EUS, although this remains hypothetical and should be validated in cohorts specifically designed to assess early- stage PDAC and high-risk populations. The relationship between diabetes and PDAC is complex and remains incompletely understood (57).

  Macrophage inhibitory cytokine 1, syncollin and thrombospondin-2 in pancreatic ductal adenocarcinoma and chronic pancreatitis differentiation · 2026 · DOI

• that reflect biological age rather Advances in high-throughput proteomics have transformed our understanding of human aging, revealing dynamic, system-level protein signatures than chronological age (Argentieri et al., 2024; Kliuchnikova et al., 2024). Despite rapid progress, several scientific, technical and translational challenges remain before proteomic biomarkers can be fully integrated into clinical practice (Haslam et al., 2022; Sissala et al., 2025). Future research must therefore focus on improving biomarker precision, expanding longitudinal datasets, advancing mechanistic interpretation, and developing clinically actionable tools for risk prediction and intervention monitoring. and assays antibody-based First, there is a critical need for standardization of proteomic platforms, protocols, and analytical pipelines (Haslam et al., 2022; Sissala et al., 2025). Differences among mass spectrometry, SomaScan, Olink, introduce substantial variability that complicates cross-study comparisons and clinical translation (Pietzner et al., 2021; Haslam et al., 2022). Future work should prioritize harmonized calibration standards, reference protein panels, and technical reproducibility benchmarks across includes establishing laboratories. This population-specific normative ranges and age-related trajectories for key proteins such as GDF15, CXCL9, NfL, IGF-1, and inflammatory cytokines. The adoption of international quality- control consortia, similar to genomics and metabolomics, will be essential to create stable cross-platform interoperability (Sissala et al., 2025). Second, future directions should focus on conducting deep longitudinal phenotyping to define individual aging trajectories (Kliuchnikova et al., 2024; Tang et al., 2025). Many current studies use cross-sectional sampling, which makes it difficult to distinguish between intra-individual and inter-individual variability. Repeated multi-timepoint measurements across decades will allow the development of personalized proteomic aging curves, identification of early divergence signals before clinical disease onset, and quantification of “resilience” after physiological stressors (Tang et al., 2025). Integrating proteomic profiles with wearables, imaging, digital phenotyping, and electronic health records will accelerate the discovery of protein markers that dynamically track functional capacity, frailty transitions, and organ-specific decline (Oh et al., 2023; Tang et al., 2025). Third, the mechanistic understanding of how circulating proteins drive or reflect aging remains incomplete (Kliuchnikova et al., 2024). Many highly predictive biomarkers, including GDF15, VCAM-1, CXCL9, matrix metallop

  Proteomics of aging: biomarkers for physiological systems and diseases · 2026 · DOI

• In summary, the integrated application of WGCNA, machine learning algorithms, immune infiltration analysis, and molecular docking allowed the identification of ENO2 and MPP1 as shared molecular markers between AD and T2DM, while VPA was identified as a candidate compound warranting further investigation.

  Integration of Bioinformatics and Machine Learning Identifies ENO2 and MPP1 as Shared Molecular Nodes Linking Alzheimer’s Disease and Type 2 Diabetes Mellitus · 2026 · DOI

• The concept that hepatic mitochondria serve not merely as metabolic engines but as command centers orchestrating inter- organ redefines our understanding of organismal aging and aging-related diseases. By decoding how communication Frontiers in Cell and Developmental Biology 19 frontiersin.org Ji et al. 10.3389/fcell.2026.1745201 TABLE 2 Summary of therapeutic strategies targeting liver-derived mitochondrial factors and their translational relevance.

  Hepatic mitochondrial signaling as a systemic hub: inter-organ communication networks in aging and aging-related diseases · 2026 · DOI

• These findings could have significant implications for further research into the mechanisms underlying diabetes and obesity, as well as potential therapeutic interventions aimed at modulating GDF-15 levels to mitigate metabolic risks.

  Investigating the Role of GDF-15 in Diabetes and Obesity: A Comprehensive Analysis of a Cohort from the KDEP Study · 2025 · DOI

• Due to its crucial roles in multiple biological processes, GDF-15 has been identified as a potential therapeutic target for various diseases. Currently, there is an ongoing recruitment for Phase I/II clinical trials investigating the impact of neutralizing GDF-15. Visugromab is an anti-GDF-15 monoclonal antibody currently being evaluated in a Phase II clinical trial as a combination therapy with the checkpoint inhibitor anti-PD-1/PD-L1 for treating advanced solid tumors. AV-380 and Ponsegromab, also anti-GDF-15 antibodies, are under evaluation as potential therapies for cancer-induced cachexia in non-small cell lung, pancreatic, and colorectal cancer patients, as well as in metastatic colorectal cancer, through Phase I and II studies. The aim of this therapeutic approach is to prevent the binding of GDF-15 to GFRAL, thereby improving anorexia and cachexia. The Phase Ib trial included 10 participants receiving Ponsegromab, with no serious adverse effects. Additionally, a gain of approximately 4,6 kg compared to baseline was achieved in 12 weeks [171]. Although the number of participants is insufficient to draw definitive conclusions, this antibody therapy represents a promising alternative for cachexia. Furthermore, the inclusion criteria include patients with the aforementioned cancer types, which may facilitate the human study of the effect of GDF-15 inhibition on tumor growth. The Phase I/II study is currently evaluating NGM120, a GFRAL antagonist antibody, on cachexia in participants with advanced pancreatic and prostate cancer. Additionally, a current application for monoclonal anti-GDF-15 is in the treatment of heart failure, with Ponsegromab undergoing recruitment in a Phase II study. Finally, a multicenter Phase II study on Visugromab is recruiting participants to assess the effects of combination therapy with Nivolumab on muscle-invasive bladder carcinoma. The Phase I/IIa clinical trial of AZD8853 in patients with metastatic solid tumors was terminated prematurely due to an overall evaluation of its risk–benefit profile. Overall, targeting GDF-15 is a very appealing therapeutic field for those pathologies where GDF-15 activity has demonstrated a clear impact, such as fibrosis-associated diseases. Conversely, animal studies on GDF-15 modulation in sepsis and cancer display significant discrepancies. Consequently, a comprehensive investigation of tissue-specific and context- dependent effects is necessary to clarify these inconsistencies. Further research should focus on deciphering the complex molecular mechanisms governing the actions of GDF-15, exploring its potential as a therapeutic target, and eluci- dating the contextual factors that impact its expression in diverse conditions. In addition, exploring the role of cell-specific receptors in mediating the effects of GDF-15 presents an exciting opportunity for further investigation. A thorough comprehension of the role of GDF-15 in fibrosis may facilitate the development of innovative therapeutic interventions and improve the clinical management of fibrotic diseases, as well as prevent the possible adverse effects of GDF-15-based therapies. Int. J. Mol. Sci. 2024, 25, 7313 19 of 28 As reviewed here, the new findings on GDF-15 in the macrophage system reveal a significant potential for displaying immunomodulatory properties in contexts involving remodeling, such as MI and fibrosis. For example, macrophages expressing GDF-15 have been suggested as a novel macrophage type with distinct transcriptomics, which medi- ates remodeling in sterile muscle injury, specifically by enhancing myoblast proliferation and decreasing inflammatory infiltration [63]. Further exploring the potential benefits of GDF-15+macrophages as an alternative to GDF-15-treated macrophages or rGDF-15 alone is very appealing. Dai et al. recently identified a naturally occurring cluster of GDF15high macrophages in the human lung. These macrophages exhibit distinct charac- teristics from M1 and M2 macrophages and express high levels of GDF-15. Additionally, they display a tolerogenic phenotype in vitro [172]. A more thorough investigation of the characteristics of this cluster is necessary to ascertain its suitability as a candidate for cell therapy with respect to functionality, plasticity, longevity, and immunogenicity. Figure 4 summarizes the reported cellular effects of GDF-15 in the macrophage system as well as its systemic interactions. Figure 4. Overview of the effects of GDF-15 in the macrophage system. Image created by bioren- der.com (accessed on 18 June 2024). Author Contributions: L.S.S.-B. writing—original draft preparation, J.G.K. and H.K.; writing—review and editing. All authors have read and agreed to the published version of the manuscript. Funding: This research received financial support from DRK-Blood Donation Service Baden- Württemberg—Hessen, Mannheim. Conflicts of Interest: The authors declare no conflict of interest.

  Macrophages as a Source and Target of GDF-15 · 2024 · DOI

• 1719451 Future multicenter prospective studies with larger sample sizes and external validation are warranted.

  Mitochondrial DNA copy number as a biomarker of oxidative stress and inflammation in premature ovarian insufficiency · 2026 · DOI

• Observing at least 4/27 responses would confirm that the drug warrants further investigation in that indication.

  Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours · 2024 · DOI

• These findings suggest that GDF-15 blockade with visugromab can overcome resistance and enhance the magnitude and durability of anti-PD-1/PD-L1 responses, and warrant further exploration in randomized trials.

  Long-term follow-up of a phase 1/2 trial of anti-GDF-15 antibody visugromab plus anti-PD-1 antibody nivolumab in anti-PD-1/-L1 relapsed/refractory solid tumors · 2026 · DOI

• However, the biological pathways underlying AF in the context of HF remain incompletely characterized.

  Proteomic signatures of atrial fibrillation in hospitalized patients with heart failure · 2026 · DOI

• Furthermore, early pregnancy GDF15 trajectories remain poorly characterised because most studies lack longitudinal sampling and rely on single or infrequent measurements.

  Early pregnancy GDF15 trajectories and their association with normal gestation, pregnancy loss, and hyperemesis gravidarum · 2026 · DOI

• The maintenance and regulation of cancer stem cell (CSC) stemness are crucial for tumor progression; however, the mechanisms underlying tumor stemness regulation remain poorly understood.

  Hypoxia-Induced TGFBI Promotes Bladder Cancer Progression by Creating a Stemness Regulation Loop through Stabilizing the Disulfide Bonds of GDF15 · 2026 · DOI

• Lifestyle factors such as a Western diet or metabolic diseases like diabetes disrupt glucose homeostasis and induce stress responses, yet their impact on skin metabolism and structural integrity remains poorly understood.

  Repression of oxidative phosphorylation by NR2F2, MTERF3 and GDF15 in human skin under high-glucose stress · 2025 · DOI

• While the biological function of pro-NAG-1/GDF15 remains unclear, our study reveals its crucial role in suppressing oncogenic signaling.

  NAG-1/GDF15 as a tumor suppressor in colorectal cancer: inhibition of β-catenin and NF-κB pathways via interaction with EpCAM · 2025 · DOI

• Abstract Gastric cancer (GC) metastasis remains a major cause of poor prognosis, yet its molecular drivers are poorly understood.

  EGR4 transcriptionally upregulates GDF15 to promote gastric cancer metastasis · 2025 · DOI

• However, the etiology and pathology of NVP have been poorly understood until recently.

  Sensitivity to fetal hormone GDF15 drives maternal risk of nausea and vomiting during pregnancy · 2025 · DOI

• Moreover, fertility is impaired in women with β-thalassemia and it remains to be demonstrated whether the reduced risk of NVP in these patients is due to other factors that may have been mistaken for prolonged exposure to GDF15.

  Sensitivity to fetal hormone GDF15 drives maternal risk of nausea and vomiting during pregnancy · 2025 · DOI

• Finally, we outline unresolved issues in GDF15 biology and therapeutics, such as the exploration of peripheral receptors, contradictory findings in studies of cardiometabolic diseases, and the persistent challenges in developing GDF15-targeted therapeutics.

  Emerging Roles of GDF15 in Metabolic and Cardiovascular Diseases · 2025 · DOI

• Nevertheless, the molecular mechanisms controlling the fate determinations of human SSCs remain elusive.

  Essential Regulation of Spermatogonial Stem Cell Fate Decisions and Male Fertility by APBB1 via Interaction with KAT5 and GDF15 in Humans and Mice · 2025 · DOI

• However, the specific function of this factor in tensile areas has not yet been investigated.

  GDF15 Contributes to the Regulation of the Mechanosensitive Responses of PdL Fibroblasts through the Modulation of IL-37 · 2024 · DOI

• The role of mitochondria peptides in the spreading of glioblastoma remains poorly understood.

  Humanin activates integrin αV–TGFβ axis and leads to glioblastoma progression · 2024 · DOI

• Previous studies on PCa cells highlighted microsomal proteins’ role in PCa progression, but their role in the progression of NEPC remains unclear.

  Proteomic Analysis of Microsomal Proteins Reveals That MVP Is Crucial for the Secretion of GDF-15, Which in Turn Promotes the Neuroendocrine Differentiation of PCa Cells · 2024 · DOI

• However, the underlying molecular mechanisms that drive these processes are not yet fully understood.

  Therapeutic role of miR-26a on cardiorenal injury in a mice model of angiotensin-II induced chronic kidney disease through inhibition of LIMS1/ILK pathway · 2024 · DOI

• While elevated GDF15 levels are linked to increased mortality risk, the role of DNA methylation (DNAm)-predicted GDF15 in predicting mortality has not been extensively studied.

  Association between DNA methylation predicted growth differentiation factor 15 and mortality: results from NHANES 1999–2002 · 2024 · DOI

Most-cited papers in GDF15 and Related Biomarkers

• Elevated Circulating Levels of Tumor Necrosis Factor in Severe Chronic Heart Failure · New England Journal of Medicine · 1990 · 2,031 citations
• Biomarkers for the diagnosis and management of heart failure · Heart Failure Reviews · 2021 · 472 citations
• Ponsegromab for the Treatment of Cancer Cachexia · New England Journal of Medicine · 2024 · 245 citations
• Atlas of the plasma proteome in health and disease in 53,026 adults · Cell · 2024 · 244 citations
• Circulating heart failure biomarkers beyond natriuretic peptides: review from the Biomarker Study Group of the Heart Failure Association ( HFA ), European Society of Cardiology ( ESC ) · European Journal of Heart Failure · 2021 · 185 citations
• GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma · Journal for ImmunoTherapy of Cancer · 2021 · 158 citations
• Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours · Nature · 2024 · 90 citations
• Plasma proteomics identify biomarkers and undulating changes of brain aging · Nature Aging · 2024 · 61 citations
• Overview of growth differentiation factor 15 (GDF15) in metabolic diseases · Biomedicine & Pharmacotherapy · 2024 · 61 citations
• PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity · Nature · 2024 · 59 citations

Most recent work

• Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia · Cancer Cell · 2026
• A GDF-15–GFRAL axis controls autoimmune T cell responses during neuroinflammation · Nature Immunology · 2026
• Mito-nuclear communication: From cellular responses to organismal health · Molecular Cell · 2026
• Growth Differentiation Factor-15 as an Emerging Biomarker in Cardiology: Diagnostic and Prognostic Implications · Journal of Personalized Medicine · 2026
• Mitochondria at the Crossroads of Cardiovascular Disease: Mechanistic Drivers and Emerging Therapeutic Strategies · Cells · 2026
• Hepatic mitochondrial signaling as a systemic hub: inter-organ communication networks in aging and aging-related diseases · Frontiers in Cell and Developmental Biology · 2026
• GDF-15 as an integrative cardiometabolic biomarker · Clinica Chimica Acta · 2026
• MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner · Free Radical Biology and Medicine · 2026
• Plasma GDF-15 Levels Are Associated With HIV Reservoir Markers Independently of Inflammation in People With HIV on Antiretroviral Therapy · The Journal of Infectious Diseases · 2026
• Potential Risks of Blocking GDF15 ‐Based Brain Energy Sensing · Journal of the American Geriatrics Society · 2026

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