Chemomechanical remodeling of glucocorticoid-sensitive fibroblasts for multimodal synergistic therapy of skin fibrosis PMID: 41707648

ADC Targets in Oncology

2026-04-10

Chemomechanical remodeling of glucocorticoid-sensitive fibroblasts for multimodal synergistic therapy of skin fibrosis

Cell Rep Med. 2026 Feb 17;7(2):102592. doi: 10.1016/j.xcrm.2026.102592.

Yifei Lu ¹ , Peng Yang ² , Weiming Gou ² , Yangping Wang ² , Li Ran ² , Lin Shi ³ , Yiming Qin ⁴ , Jingyuan Li ⁵ , Ning Zhang ⁶ , Dongdong Xue ² , Ming Ao ² , Zhan Shu ² , Xingyue Zhang ⁷ , Yaqin Zhou ² , Ling Huang ² , Dengfeng He ² , Xiaorong Zhang ² , Yong Huang ² , Haisheng Li ² , Junyi Zhou ⁸ , Jianglin Tan ⁹ , Qing Zhang ¹⁰ , Gaoxing Luo ¹¹

Affiliations

1. Institute of Burn Research, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory for Disease Proteomics, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China; Army 953th Hospital (Shigatse Branch, Xinqiao Hospital), Army Medical University (Third Military Medical University), Shigatse 857000, China.
2. Institute of Burn Research, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory for Disease Proteomics, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China.
3. Chongqing Municipal Institute of Tuberculosis, Chongqing 400050, China.
4. Department of Dermatology and Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
5. Department of Pathology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China.
6. School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
7. Department of Dermatology, The Seventh Medical Center of Chinese PLA General Hospital, Beijing 100700, China.
8. Institute of Burn Research, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory for Disease Proteomics, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: [email protected].
9. Institute of Burn Research, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory for Disease Proteomics, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: [email protected].
10. Institute of Burn Research, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory for Disease Proteomics, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: [email protected].
11. Institute of Burn Research, State Key Laboratory of Trauma and Chemical Poisoning, Chongqing Key Laboratory for Disease Proteomics, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: [email protected].

Abstract

Challenges and opportunities in multimodal synergistic therapy for skin fibrosis encompass elucidating the mechanisms of synergistic treatment, optimizing and developing highly coupled combinations, and eliminating therapeutic resistance. This study reveals that the excessively deposited extracellular matrix of hypertrophic scar not only forms a physical barrier for local drug delivery but also generates high mechanical stress, which drives glucocorticoid insensitivity by activating the FAK-AKT-HDAC2 axis in fibroblasts. Both mechanical and biological barriers result in poor outcomes of triamcinolone acetonide therapy for hypertrophic scars. To address this, a chemomechanical antifibrotic approach is engineered by integrating a microneedle-based transdermal delivery platform, immobilized Enzymes, and long-acting sustained-release microspheres. This strategy significantly sensitizes scar fibroblasts by disrupting the fibrotic extracellular matrix and the resultant mechanics-induced cellular programs for drug resistance, thus notably reversing the fibrotic characteristics. These findings uncover a mechanism of glucocorticoid resistance and present a multimodal, self-administrable therapy against fibrosis.

Keywords

extracellular matrix stiffness; fibrosis; glucocorticoid insensitivity; hypertrophic scar; mechanical microenvironment; microneedle.