Cyclin-Dependent Kinase Inhibitor 1A Betrays Early Liver Damage Driving Cancer: A Pilot Study
Year: 2026
Type: article
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.
Authors: Ari Sánchez-Padilla, Amairani Escorcia-Barrera, Marco Antonio Tafoya-Olvera, Alejandra Idan Valencia-Cruz, José Luis García-Meza, Brisa Rodope Alarcón-Sánchez, Osiris Germán Idelfonso-García, Linda Vanessa Márquez-Quiroga, Julia Esperanza Torres-Mena, Sergio Fuentes-Hernández, Lorena Lizbeth Valderrama-Cervantes, Ema Elvira Herrera-López, Isaac Aguirre-Maldonado, José Jaime Martínez-Magaña, Osbaldo Resendis-Antonio, Erick Andrés Muciño-Olmos, Diana Ivette Aparicio-Bautista, Gustavo Basurto-Islas, Sergio Agustín Román-González, María Angélica Gutiérrez-Nava, Alfredo Mendoza-Vargas, Mónica Noemí Jiménez-García, Ruth Pacheco-Rivera, Gabriela Gutiérrez-Reyes, José Luis Pérez-Hernández, Saúl Villa-Treviño, Rafael Baltiérrez-Hoyos, Verónica Rocío Vásquez-Garzón, Pablo Muriel, Julio Isael Pérez-Carreón, Jaime Arellanes-Robledo
Institutions: National Institute of Genomic Medicine, Benito Juárez Autonomous University of Oaxaca, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Universidad Autónoma Metropolitana, Secretaría de Ciencia, Humanidades, Tecnología e Innovación, Universidad Nacional Autónoma de México, United States Department of Veterans Affairs, Yale University, VA Connecticut Healthcare System, National Center for Post Traumatic Stress Disorder, Lund University, Universidad de Guanajuato, Instituto Politécnico Nacional, Hospital General de México
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,499
OpenAlex ID: W7225802966