Therapies Targeting Metabolic Pathways in Lung Fibrosis: Advances and Future Perspectives

Abstract

Pulmonary fibrosis is a progressive lung disease associated with high morbidity and mortality. Increasing evidence indicates that metabolic reprogramming is a central driver of fibrogenesis. Multiple cell types in the fibrotic lung, including fibroblasts, alveolar epithelial type II (AEC2) cells, and macrophages, exhibit enhanced glycolysis, dysregulated lipid turnover, and altered amino acid utilization. These metabolic changes promote fibroblast activation, sustain ECM production, and impair epithelial repair. Recent studies have identified key regulatory pathways—such as hypoxia-inducible factor-1α(HIF-1α)-mediated glycolysis, aberrant fatty acid and cholesterol metabolism, and glutamine-dependent anabolic processes—that collectively shape the profibrotic microenvironment. Targeting these metabolic vulnerabilities has shown promising antifibrotic effects in preclinical studies, supporting glycolysis inhibitors, lipid-modulating agents, and amino acid metabolism blockers as potential therapeutic approaches. This review summarizes recent advances in glucose, lipid, and amino acid metabolic reprogramming in pulmonary fibrosis, with IPF discussed as a representative and well-studied subtype, and highlights emerging metabolic-targeted therapeutic strategies. Understanding cell-specific metabolic adaptations may provide new opportunities to develop effective interventions for pulmonary fibrosis, whereas most metabolic mechanisms are shared across fibrotic lung diseases.

Keywords

Pulmonary fibrosis / Metabolic reprogramming / Glucose metabolism / Lipid metabolism / Amino acid metabolism / Targeted therapy

Statement of the Use of Generative AI and AI-Assisted Technologies in the Writing Process

During the preparation of this manuscript, the authors used ChatGPT (version 4.0) solely for grammar checking. After using this tool, the authors reviewed and edited the content as needed and assume full responsibility for the content of the published article.

Acknowledgments

The authors would like to thank all researchers whose work contributed to this review.

Author Contributions

Conceptualization, Y.W.; Methodology, Y.W.; Software, Y.W.; Validation, Y.Z. (Yanlin Zhou), and Y.Z. (Yilin Zhang), and J.L.; Formal Analysis, Y.Z. (Yanlin Zhou); Investigation, Y.Z. (Yanlin Zhou); Resources, Y.W. and Y.Z. (Yanlin Zhou); Data Curation, Y.Z. (Yilin Zhang) and J.L.; Writing—Original Draft Preparation, Y.W.; Writing—Review & Editing, Y.W.; Visualization, Y.W.; Supervision, G.Y. and L.W.; Project Administration, G.Y. and L.W.; Funding Acquisition, G.Y. and L.W.

Ethics Statement

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

No new data were generated or analyzed in this study. Data sharing is not applicable to this article.

Funding

This study was supported by the National Natural Science Foundation of China（Grant Number 32570921 to L.W.), State Innovation Base for Pulmonary Fibrosis (111 Project) , Key R&D Program of Henan province, China (231111310400 to G.Y.), Zhongyuan scholar, Henan, China (244000510009 to G.Y.), and Henan Project of Science and Technology, China (GZS2023008, 242102311167, 252102520084).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

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