Cyclin-Dependent Kinase Inhibitor 1A Betrays Early Liver Damage Driving Cancer: A Pilot Study

Hepatocellular carcinoma (HCC) progresses asymptomatically over several decades after chronic exposure to multiple hepatotoxins. Here, we aimed to identify molecules revealing the malignant onset and progression of liver diseases. From a transcriptomic analysis of a HCC mouse model, ingenuity pathway analysis (IPA) was used to determine the involved causal signaling networks, and relevant genes were validated to identify early biomarkers. The relevant findings were validated in the blood of high-fat diet, alcohol-associated liver disease (ALD), and metabolic dysfunction-associated steatotic liver disease (MASLD) in vivo models, as well as in ALD patients. Ten IPA-predicted causal signaling networks were associated with HCC progression. The expression of cyclin-dependent kinase inhibitor 1a (Cdkn1a) gene, commonly known as P21, was the most dysregulated, and its total (CDN1A/P21) and phosphorylated protein level was increased from early to late stages. P21 was also increased and released into the bloodstream of ALD and MASLD models, both based on multiple hepatotoxins linked to HCC development, as well as in the bloodstream of ALD patients. In conclusion, P21 is altered from early stages of liver diseases leading to HCC, which betrays the onset of liver cancer before developing malignant traits; thus, P21 offers a critical therapeutic window for timely detection of high-risk patients.

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Journal
International Journal of Molecular Sciences
Published
2026-11-11
DOI
https://doi.org/10.3390/ijms272210114
Primary Topic
Hepatocellular Carcinoma Treatment and Prognosis
Type
article
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article

Cyclin-Dependent Kinase Inhibitor 1A Betrays Early Liver Damage Driving Cancer: A Pilot Study

Sergio Fuentes-Hernández, Julio Isael Pérez‐Carreón, Alejandra Idan Valencia-Cruz, Osiris Germán Idelfonso-García et al.
International Journal of Molecular Sciences
Hepatocellular Carcinoma Treatment and Prognosis
article

Cyclin-Dependent Kinase Inhibitor 1A Betrays Early Liver Damage Driving Cancer: A Pilot Study

Sergio Fuentes-Hernández, Julio Isael Pérez‐Carreón, Alejandra Idan Valencia-Cruz, Osiris Germán Idelfonso-García, Alfredo Mendoza-Vargas, Pablo Muriel, Osbaldo Reséndis-Antonio, José Luis Pérez-Hernández, Sergio Agustín Román-González, Gustavo Basurto‐Islas, Mónica Noemí Jiménez-García, Linda Vanessa Márquez-Quiroga, Rafael Baltiérrez‐Hoyos, Julia Esperanza Torres‐Mena, María Angélica Gutiérrez‐Nava, Verónica Rocío Vásquez-Garzón, Ema Elvira Herrera-López, Saúl Villa‐Treviño, Erick Andrés Muciño-Olmos, Jaime Arellanes‐Robledo, Brisa Rodope Alarcón‐Sánchez, José Jaime Martínez‐Magaña, Gabriela Gutiérrez‐Reyes, Isaac Aguirre-Maldonado, Diana I. Aparicio‐Bautista, Ruth Pacheco-Rivera, Marco Antonio Tafoya-Olvera, José Luis García-Meza, Amairani Escorcia-Barrera, Ari Sánchez-Padilla, Lorena Lizbeth Valderrama-Cervantes
article en

Abstract

Hepatocellular carcinoma (HCC) progresses asymptomatically over several decades after chronic exposure to multiple hepatotoxins. Here, we aimed to identify molecules revealing the malignant onset and progression of liver diseases. From a transcriptomic analysis of a HCC mouse model, ingenuity pathway analysis (IPA) was used to determine the involved causal signaling networks, and relevant genes were validated to identify early biomarkers. The relevant findings were validated in the blood of high-fat diet, alcohol-associated liver disease (ALD), and metabolic dysfunction-associated steatotic liver disease (MASLD) in vivo models, as well as in ALD patients. Ten IPA-predicted causal signaling networks were associated with HCC progression. The expression of cyclin-dependent kinase inhibitor 1a (Cdkn1a) gene, commonly known as P21, was the most dysregulated, and its total (CDN1A/P21) and phosphorylated protein level was increased from early to late stages. P21 was also increased and released into the bloodstream of ALD and MASLD models, both based on multiple hepatotoxins linked to HCC development, as well as in the bloodstream of ALD patients. In conclusion, P21 is altered from early stages of liver diseases leading to HCC, which betrays the onset of liver cancer before developing malignant traits; thus, P21 offers a critical therapeutic window for timely detection of high-risk patients.

International Journal of Molecular SciencesVol. 27(22)
Universidad de Guanajuato (MX), United States Department of Veterans Affairs (US), Lund University (SE), Universidad Autónoma Metropolitana (MX), Hospital General de México (MX), Yale University (US), VA Connecticut Healthcare System (US), National Institute of Genomic Medicine (MX), National Center for Post Traumatic Stress Disorder (US), Secretaría de Ciencia, Humanidades, Tecnología e Innovación (MX), Instituto Politécnico Nacional (MX), Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (MX), Universidad Nacional Autónoma de México (MX), Benito Juárez Autonomous University of Oaxaca (MX)
Hepatocellular Carcinoma Treatment and Prognosis
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