Fibrosis, characterised by the excessive deposition of extracellular matrix via activated fibroblasts, is a pathological feature of several chronic inflammatory disorders, which collectively contribute significantly to global morbidity and mortality. Despite this, current anti-fibrotic therapies are of limited efficacy. However, incretin-based therapies, primarily glucagon-like peptide-1 (GLP-1) receptor agonists, are now emerging as candidate drugs for modulating fibrotic signalling pathways. This review synthesises the growing body of preclinical and clinical evidence that incretin receptor agonists exert direct and indirect anti-fibrotic effects. We detail the molecular mechanisms and survey the promising data across hepatic, cardiac, renal, lung, and joint tissues, which underscore the potential for repurposing of this drug class as a therapeutic strategy for fibro-inflammatory conditions.
Today’s society has gradually entered an aging phase, and among the elderly population, the risk of chronic kidney disease (CKD) is significantly increased. Renal fibrosis is the key pathological mechanism for the development of chronic kidney disease to end-stage renal disease. With the increase in age, the phenomenon of glomerular sclerosis and interstitial fibrosis in aging kidneys gradually aggravates, and the glomerular filtration rate (GFR) decreases, further affecting renal function. Fibrosis not only accelerates the loss of renal function but also significantly increases the risk of cardiovascular disease, which seriously affects the quality of life and life expectancy of patients. This paper reviews the relevant literature and discusses the characteristics of an aging kidney and the diagnostic methods for renal fibrosis.
Modafinil (MF) is a clinically approved wake-promoting agent with emerging anti-inflammatory and anti-fibrotic effects, although its upstream molecular target has remained undefined. Here, we identify adenosine deaminase (ADA) as a previously unrecognized target mediating the therapeutic actions of MF. Its S- and R-isomers (MF-S and MF-R) robustly increased intracellular cAMP levels in fibroblasts with efficacy comparable to NECA, despite minimal direct binding to adenosine receptors, and suppressed KCa3.1 channel activity via a PKA–dependent mechanism. MF-S markedly upregulated CD39 and CD73, leading to increased adenosine availability. Pharmacological inhibition of CD73 with AB680 abolished MF-S–induced increases in cAMP and Epac levels and reversed suppression of TGFβ–induced collagen expression. Consistently, MF-S attenuated canonical profibrotic signaling by inhibiting TGFβ–induced Smad4 upregulation. In vivo, MF-S significantly reduced hypertrophic scarring in a rabbit ear model, with efficacy comparable to Contratubex. Mechanistically, MF-S directly inhibited purified ADA at subnanomolar concentrations and suppressed cellular ADA activity in fibroblast and immune cells. Collectively, these findings establish ADA inhibition as a key upstream mechanism by which MF enhances adenosine–cAMP signaling to suppress inflammation and fibrosis, highlighting MF and its isomers as promising therapeutic candidates for inflammatory and fibrotic diseases.
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.
Several studies have attempted to clarify the role of exosomes and/or microvesicles derived from mesenchymal stromal cells (MSCs) (collectively indicated as extracellular vesicles: MSCs-EVs) in pulmonary fibrosis. Depending on their origin and on the micro-environmental context, MSCs-EVs may support or attenuate the fibrotic invasion of the lung, a hallmark of all Interstitial Lung Diseases (ILDs). Indeed, EVs have emerged as pivotal intercellular mediators and their potential diagnostic and therapeutic applications have been suggested. We aim here to elucidate the dual role of MSCs-derived exosomes and microvesicles: the contribution to pulmonary fibrosis progression, exerted by the MSCs-EVs originated from resident MSCs, or the potential therapeutic activity of those generated from healthy MSCs. Actually, MCSs-EVs appear as the frontiers of cell-free therapy and nano-medicine research in a great number of pre-clinical studies, but developments are needed to optimize and standardize their isolation, production and delivery. Interestingly, since the respiratory system directly communicates with the external environment, lung treatment could be approached by MSCs-EVs nebulization as a preferential administration route, integrating targeted pulmonary delivery with an enhanced patient’s compliance. Hence MSCs-EVs may contribute to ILD pathogenesis, display a potential as biomarkers, and still hold promise as therapeutic agents to reduce lung fibrosis. However further researches are needed to validate their clinical application.
