Evidence mapPaperPMID 40959856Full record

ArticleHistology and histopathology2025

Differential expression of ferroptosis markers, circadian regulators, KLOTHO, and classical tumor suppressors in colorectal cancer according to tumor stage: Influence of age, anatomical location, and correlation patterns.

Miguel A Saez, Cielo Garcia-Montero, Oscar Fraile-Martinez, Ana M Minaya-Bravo, Diego Liviu Boaru, Diego De Leon-Oliva, Patricia De Castro-Martinez, Majd N Michael Alhaddadin, Silvestra Barrena-Blázquez, Laura Lopez-Gonzalez and 13 more

Abstract read
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In one paragraph

Article in Histology and histopathology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

23 authors.

Miguel A SaezDepartment of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), University of Alcalá, Alcalá de Henares, Spain.
Cielo Garcia-MonteroDepartment of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), University of Alcalá, Alcalá de Henares, Spain.
Oscar Fraile-MartinezDepartment of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), University of Alcalá, Alcalá de Henares, Spain.
Ana M Minaya-BravoDepartment of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), University of Alcalá, Alcalá de Henares, Spain.
Diego Liviu BoaruDepartment of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), University of Alcalá, Alcalá de Henares, Spain.
Diego De Leon-OlivaDepartment of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), University of Alcalá, Alcalá de Henares, Spain.
Patricia De Castro-MartinezDepartment of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), University of Alcalá, Alcalá de Henares, Spain.
Majd N Michael AlhaddadinDepartment of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), University of Alcalá, Alcalá de Henares, Spain.
Silvestra Barrena-BlázquezRamón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain.
Laura Lopez-GonzalezRamón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain.
Luis G GuijarroRamón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain.
Natalio Garcia-HonduvillaDepartment of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), University of Alcalá, Alcalá de Henares, Spain.
Víctor Roberto Baena RomeroPathological Anatomy Service, Central University Hospital of Defence-UAH Madrid, Alcalá de Henares, Spain.
Carlos Daniel Padilla AnsalaPathological Anatomy Service, Central University Hospital of Defence-UAH Madrid, Alcalá de Henares, Spain.
Mar RoyuelaRamón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain.
María Del Val Toledo LoboRamón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain.
Leonel PekarekDepartment of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), University of Alcalá, Alcalá de Henares, Spain.
Roberto Fernández-Baillo Gallego de la SacristanaRamón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain.
Mauricio Hernández-FernándezRamón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain.
Montserrat Chao CrecentePathological Anatomy Service of the "Severo Ochoa" University Hospital, Leganés, Spain.
Melchor Alvarez-MonDepartment of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD), University of Alcalá, Alcalá de Henares, Spain.
Raul Diaz-PedreroRamón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain.
Miguel A OrtegaRamón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain.

Funding

Comunidad de Madrid P2022/BMD-7321HALE KULANI, S. L.MJRProACapital
6 · The paper itself

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related mortality, with an incidence projected to rise significantly worldwide. While TNM staging remains the cornerstone of prognosis and treatment decisions, additional biomarkers are needed to enhance predictive accuracy and therapeutic targeting. Ferroptosis, an iron-dependent cell death pathway, has emerged as a key regulator of CRC progression and therapy resistance. Circadian rhythms, KLOTHO, and tumor suppressors, such as p53, CDKN1A (p21), and Rb, also play crucial roles in CRC biology. Integrating TNM staging with molecular markers and patient-specific variables offers a more precise, personalized approach to CRC management. In the present work, we analyze the histopathological expression of KLOTHO, ferroptosis markers (TFRC, ALOX-5, ACSL-4, and GPX-4), circadian regulators (CLOCK, BMAL1, PER1, and PER2), and classical tumor suppressors (p53, p21, and Rb) in a cohort of 63 patients diagnosed with CRC. Besides, we have considered important clinical variables, like sex, age, and anatomical location, in our statistical analysis; correlation with the protein expression of these markers was also included for each stage (T1, T2, and T3). Our study reveals that advanced CRC stages (primarily T3) exhibit increased expression of ferroptosis markers (TFRC, ALOX5, ACSL4, and GPX4) and tumor suppressors (p53, p21, and Rb), alongside reduced histopathological detection of KLOTHO and circadian markers (BMAL1, CLOCK, PER1, and PER2) compared with earlier stages. Age, but not sex, influenced the expression of several markers. Tumor location also played a role, with right-sided CRCs showing significant stage-related differences in ferroptosis, tumor suppressor, and BMAL1, whereas left-sided tumors exhibited variations primarily in circadian markers (CLOCK, PER1, and PER2). Correlation analyses across tumor stages indicate dynamic shifts, with tumor suppressors maintaining positive associations with ferroptosis markers and anti-aging/circadian markers showing stage-dependent changes. Despite the inherent limitations of our study, these findings highlight the evolving biomarker landscape in CRC progression, although further research is needed to elucidate their clinical implications.

Indexed as

Biomarkers, TumorColorectal NeoplasmsFerroptosisGlucuronidaseAdultAgedAged, 80 and overAge FactorsCircadian RhythmFemaleHumansKlotho ProteinsMaleMiddle AgedNeoplasm StagingBiomarkers, TumorGlucuronidaseKlotho Proteins

Identifiers

PMID40959856

What Socratic holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.