ORIGINAL RESEARCH article
Front. Bioeng. Biotechnol.
Sec. Tissue Engineering and Regenerative Medicine
This article is part of the Research TopicApplication of Tissue Engineering in Bone, Joints, Ligaments Injuries and Cartilage RegenerationView all 18 articles
High-throughput 3D phenotypic screening identifies repurposed MEK inhibitors as drivers of chondrogenesis for cartilage regeneration
Provisionally accepted
Hadi Hajiali1*
Justyna Cholewa-Waclaw2Jacob Ballard1
Kerime Ebrar Okur1Richard Elliott2
Neil O Carragher2
Alicia Jennifer El Haj1- 1University of Birmingham, Birmingham, United Kingdom
- 2The University of Edinburgh, Edinburgh, United Kingdom
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Abstract Background and Purpose Chondrogenesis is essential for cartilage repair and regeneration, particularly in treating osteoarthritis and cartilage injuries. While conventional therapies rely heavily on growth factors, recent interest has turned toward drug repurposing strategies involving small-molecule inhibitors. This study aims to evaluate the chondrogenic potential of selected bioactive compounds, with a particular focus on Trametinib, a MEK inhibitor. Experimental Approach A library of 55 bioactive compounds was screened using high-content imaging and a 3D hydrogel model that mimics the native cartilage microenvironment. Cellular morphology, migration, and cytoskeletal organization were assessed to identify chondrogenic phenotypes. Trametinib, along with Panobinostat, SAHA, and Brefeldin A, was further evaluated via dose-response analyses and molecular assays to determine their impact on chondrogenic differentiation. Key Results Trametinib was identified as a potent modulator of chondrogenesis-related cellular phenotypes. It significantly altered cell morphology, promoted a chondrogenic-like shape, and enhanced cell migration. Changes in actin organization were quantified using SER-Spot and SER-Ridge metrics, showing patterns consistent with chondrogenic differentiation. Molecular analysis revealed upregulation of Collagen II and aggrecan, key markers of cartilage formation. Conclusions and Implications These findings support the potential of MEK inhibitors like Trametinib, and other selected bioactive compounds, as promising agents for cartilage regeneration. Their repurposing could offer innovative therapeutic strategies for treating cartilage-related disorders, including osteoarthritis.
Keywords: 3D cartilage regeneration, Chondrogenesis, drug repurposing, High-throughput drug screening, mek inhibitor, trametinib
Received: 17 Nov 2025; Accepted: 09 Feb 2026.
Copyright: © 2026 Hajiali, Cholewa-Waclaw, Ballard, Okur, Elliott, Carragher and El Haj. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Hadi Hajiali
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