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Review

Mechanotransduction-Epigenetic Coupling in Pulmonary Regeneration: Multifunctional Bioscaffolds as Emerging Tools

1
Department of Physiology, School of Medicine, Southeast University, Nanjing 210009, China
2
Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
3
Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2025, 18(10), 1487; https://doi.org/10.3390/ph18101487
Submission received: 2 September 2025 / Revised: 27 September 2025 / Accepted: 30 September 2025 / Published: 2 October 2025
(This article belongs to the Section Pharmacology)

Abstract

Pulmonary fibrosis (PF) is a progressive and fatal lung disease characterized by irreversible alveolar destruction and pathological extracellular matrix (ECM) deposition. Currently approved agents (pirfenidone and nintedanib) slow functional decline but do not reverse established fibrosis or restore functional alveoli. Multifunctional bioscaffolds present a promising therapeutic strategy through targeted modulation of critical cellular processes, including proliferation, migration, and differentiation. This review synthesizes recent advances in scaffold-based interventions for PF, with a focus on their dual mechano-epigenetic regulatory functions. We delineate how scaffold properties (elastic modulus, stiffness gradients, dynamic mechanical cues) direct cell fate decisions via mechanotransduction pathways, exemplified by focal adhesion–cytoskeleton coupling. Critically, we highlight how pathological mechanical inputs establish and perpetuate self-reinforcing epigenetic barriers to regeneration through aberrant chromatin states. Furthermore, we examine scaffolds as platforms for precision epigenetic drug delivery, particularly controlled release of inhibitors targeting DNA methyltransferases (DNMTi) and histone deacetylases (HDACi) to disrupt this mechano-reinforced barrier. Evidence from PF murine models and ex vivo lung slice cultures demonstrate scaffold-mediated remodeling of the fibrotic niche, with key studies reporting substantial reductions in collagen deposition and significant increases in alveolar epithelial cell markers following intervention. These quantitative outcomes highlight enhanced alveolar epithelial plasticity and upregulating antifibrotic gene networks. Emerging integration of stimuli-responsive biomaterials, CRISPR/dCas9-based epigenetic editors, and AI-driven design to enhance scaffold functionality is discussed. Collectively, multifunctional bioscaffolds hold significant potential for clinical translation by uniquely co-targeting mechanotransduction and epigenetic reprogramming. Future work will need to resolve persistent challenges, including the erasure of pathological mechanical memory and precise spatiotemporal control of epigenetic modifiers in vivo, to unlock their full therapeutic potential.
Keywords: multifunctional scaffolds; mechanobiology; epigenetic regulation; pulmonary fibrosis; CRISPR/dCas9s; lung regeneration; biomaterials; mechanotransduction; tissue engineering multifunctional scaffolds; mechanobiology; epigenetic regulation; pulmonary fibrosis; CRISPR/dCas9s; lung regeneration; biomaterials; mechanotransduction; tissue engineering

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MDPI and ACS Style

Wang, J.; Xu, A. Mechanotransduction-Epigenetic Coupling in Pulmonary Regeneration: Multifunctional Bioscaffolds as Emerging Tools. Pharmaceuticals 2025, 18, 1487. https://doi.org/10.3390/ph18101487

AMA Style

Wang J, Xu A. Mechanotransduction-Epigenetic Coupling in Pulmonary Regeneration: Multifunctional Bioscaffolds as Emerging Tools. Pharmaceuticals. 2025; 18(10):1487. https://doi.org/10.3390/ph18101487

Chicago/Turabian Style

Wang, Jing, and Anmin Xu. 2025. "Mechanotransduction-Epigenetic Coupling in Pulmonary Regeneration: Multifunctional Bioscaffolds as Emerging Tools" Pharmaceuticals 18, no. 10: 1487. https://doi.org/10.3390/ph18101487

APA Style

Wang, J., & Xu, A. (2025). Mechanotransduction-Epigenetic Coupling in Pulmonary Regeneration: Multifunctional Bioscaffolds as Emerging Tools. Pharmaceuticals, 18(10), 1487. https://doi.org/10.3390/ph18101487

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