Growth differentiation factor 11 modulates metabolism, mitigating the pro-tumoral behavior provided by M2-like macrophages in hepatocellular carcinoma-derived cells

doi:10.3748/wjg.v31.i40.111307

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Oct 28, 2025 (publication date) through Feb 26, 2026

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Basic Study

World J Gastroenterol. Oct 28, 2025; 31(40): 111307
Published online Oct 28, 2025. doi: 10.3748/wjg.v31.i40.111307

Growth differentiation factor 11 modulates metabolism, mitigating the pro-tumoral behavior provided by M2-like macrophages in hepatocellular carcinoma-derived cells

Alejandro Escobedo-Calvario, Lisette Chávez-Rodríguez, Verónica Souza-Arroyo, Leticia Bucio-Ortiz, Roxana U Miranda-Labra, Felipe Masso, Araceli Páez-Arenas, Rogelio Hernández-Pando, Jens Marquardt, María Concepción Gutiérrez-Ruiz, Luis E Gomez-Quiroz

Alejandro Escobedo-Calvario, Lisette Chávez-Rodríguez, Verónica Souza-Arroyo, Leticia Bucio-Ortiz, Roxana U Miranda-Labra, María Concepción Gutiérrez-Ruiz, Luis E Gomez-Quiroz, Department of Ciencias de la Salud, Universidad Autónoma Metropolitana, Mexico City 09340, Ciudad de México, Mexico

Felipe Masso, Araceli Páez-Arenas, Unidad de Medicina Traslacional, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Ciudad de México, Mexico

Rogelio Hernández-Pando, Department of Pathology, National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico City 14080, Ciudad de México, Mexico

Jens Marquardt, Department of Medicine, University of Lübeck, Lübeck 23552, Schleswig-Holstein, Germany

Co-corresponding authors: María Concepción Gutiérrez-Ruiz and Luis E Gomez-Quiroz.

Author contributions: Escobedo-Calvario A performed experiments; Escobedo-Calvario A, Chávez-Rodríguez L, Souza-Arroyo V, Bucio-Ortiz L, Hernández- Pando R, Marquardt J, and Gutiérrez-Ruiz MC contributed to methodology; Escobedo-Calvario A and Chávez-Rodríguez L contributed to investigation; Escobedo-Calvario A, Souza-Arroyo V, Bucio-Ortiz L, Masso F, Páez-Arenas A, and Gutiérrez-Ruiz MC contributed to writing; Souza-Arroyo V designed the biostatistical analysis; Bucio-Ortiz L obtained the funding; Miranda-Labra RU performed the reactive oxygen species studies; Masso F and Páez-Arenas A contributed to flow cytometry analysis; Hernández-Pando R and Marquardt J reviewed the manuscript; Gomez-Quiroz LE performed the conceptualization, project administration, initial draft preparation, and paper submission. All authors approved the final version of the article.

Institutional review board statement: The study was reviewed and approved by the Graduate Program in Experimental Biology at the Metropolitan Autonomous University.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

Data sharing statement: The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Corresponding author: Luis E Gomez-Quiroz, PhD, Department of Ciencias de la Salud, Universidad Autónoma Metropolitana Iztapalapa, No. 186 San Rafael Atlixco, Mexico City 09340, Ciudad de México, Mexico. legq@xanum.uam.mx

Received: June 27, 2025
Revised: July 24, 2025
Accepted: September 23, 2025
Published online: October 28, 2025
Processing time: 122 Days and 12.3 Hours

Core Tip

Core Tip: Hepatocellular carcinoma (HCC) is an aggressive tumor, and the infiltration of tumor-associated macrophages or M2-like macrophages increases aggressiveness. We need therapies to mitigate this pathology in the immune context. In the present study, our in vitro model demonstrates that growth differentiation factor 11 (GDF11) counteracts the pro-tumorigenic properties of M2-like macrophages. This was shown in the reduction of cluster of differentiation 206; furthermore, it induces changes in metabolism and the redox state. Conditioned media from GDF11-treated M2-like macrophages possessed changes in their cytokine profile that neutralized the proliferation and migration of HCC cells, demonstrating that GDF11 alters the pro-tumoral properties of macrophages. This study suggests that mitigating tumor-associated macrophages may be an effective strategy for controlling HCC.