Regenerative Therapies in the Treatment of Idiopathic Pulmonary Fibrosis: A Literature Review

Janislene S Ferreira; Gislaine Mito; Elaine Hermenegildo

doi:doi:10.11648/j.ajcem.20251304.15

Research Article |

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Regenerative Therapies in the Treatment of Idiopathic Pulmonary Fibrosis: A Literature Review

Janislene S Ferreira^*

, Gislaine Mito

, Elaine Hermenegildo

Published in American Journal of Clinical and Experimental Medicine (Volume 13, Issue 4)

Received: 18 August 2025 Accepted: 18 August 2025 Published: 18 August 2025

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Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a disease that leads to respiratory failure and subsequent death. To prevent chronic lung diseases from rising further up the list of leading causes of death worldwide, new innovative therapeutic approaches are needed. This work aims to present a literature review on advances in regenerative therapies in the treatment of IPF. The bibliographic strategy of this research used papers published in last ten years taken from the electronic databases PubMed and Capes Periodical Portal, which include the current understanding of this pathology, and the different treatment modalities. The majority of selected articles were concentrated in the last three years of this review, corroborating the expectation of recent advancements given the current massive scientific research on IPF. This review focused on current treatments, their limitations and investigated cutting-edge research in regenerative therapies. The research resulted in the presentation of ongoing studies and therapies segregated between pharmacological manipulation and the use of stem cells. Both categories of treatment focus on restoring endogenous lung repair or targeting pathways that inhibit dysregulated regeneration. Genetic and epigenetic factors were constantly highlighted as extremely necessary for the diagnosis. Conclusively, given the heterogeneity of this pathology, the authors propose, for the next general IPF treatment protocol, the inclusion of a combination of therapies, accentuating the pro and post-installed disease components. Encouraging the established of specialized health centers is also part of the findings of this research. They promote close cooperation between pulmonologists, radiologists, biomedical geneticists, pathologists, among others.

Published in	American Journal of Clinical and Experimental Medicine (Volume 13, Issue 4)
DOI	10.11648/j.ajcem.20251304.15
Page(s)	99-134
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2025. Published by Science Publishing Group

Keywords

Idiopathic Pulmonary Fibrosis, Therapeutic Approach, Regenerative Therapies

1. Introduction

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and devastating interstitial lung disease, restricted to the lungs, with no clearly known etiological cause, receiving the name Idiopathic

[17]

. It mainly affects adult patients, over 50 years old and in a proportion of 2-3 men to 1 woman

[3]

. In Brazil, Baddini-Martinez and Pereira estimated, based on data from the USA, an annual incidence of 3.5-5.1/100,000 inhabitants and a prevalence of 7.1-9.4/100,000 inhabitants

[5]

. Mortality is high, and most patients have an estimated survival of 3-5 years without treatment.

Possible factors causing pulmonary fibrosis include smoking, exposure to environmental impurities, occupational risks such as asbestos dust or silica, inhalation of toxic gases, certain medications, autoimmune diseases, genetic factors, aging, and idiopathic causes. Other risk factors and related complications include pulmonary emphysema, gastroesophageal reflux disease, obstructive sleep apnea, and chronic viral infections

[3]

IPF occurs due to the thickening and scarring of lung tissues, leading to impaired lung function or insufficient breathing. This disease involves the generation of scar tissue in the lungs, which dominates the thickening and stiffening of the lung walls, resulting in a loss of flexibility, making it difficult to supply oxygen to the bloodstream effectively.

The most common signs and symptoms of IPF are persistent dry cough and progressive dyspnea on exertion. Lung crackles and clubbing may also be present. The diagnosis is made by excluding some diseases and may begin with checking different symptoms and conducting some tests to reach a final diagnosis. Among the tests, high-resolution computed tomography, surgical lung biopsy or both stand out

[19]

Among the current treatments to help control the progression of the disease, and provide comfort for the patient, are corticosteroids, immunosuppressants, oxygen therapy, lung transplantation and antifibrotic medications. Antifibrotics, including Nintedanib and Pirfenidone, aim to reduce inflammation and slow healing in the lungs. Although they do not cure, they can help prolong life, but they have side effects

[26]

IPF treatment is constantly evolving. Future perspectives in the management of IPF are focused on the development of more effective therapies that aim not only to slow the progression of the disease, but to reverse pulmonary fibrosis. Challenges for this treatment include early diagnosis, disease heterogeneity and lack of curative treatments

[34]

Regenerative medicine works to restore and repair tissues, organs, and functions of the human body. It seeks to develop therapies and approaches to replace or regenerate damaged cells, tissues, and organs. The main objective is to restore the body's normal function. In this sense, stem cells play a crucial role

[1]

In addition to stem cells, other regenerative medicine approaches include the use of biomaterials, nano therapy, gene therapy, cell therapy, and tissue engineering

[37]

Numerous research studies link susceptibility to IPF to various genetic and epigenetic factors and potential contributions of variants and interactions

[37, 26, 22]

. Although the real etiology of IPF is not completely known, there is evidence that it is inherited in an autosomal dominant manner with variable penetrance and represents 2% to 20% of all cases of idiopathic interstitial pneumonia

[32]

Aging is an important risk factor in the disease, with mitochondria being prominent in its onset and progression. There are currently therapeutic approaches focused on improving mitochondrial dysfunction

[10]

According to statistics from the Synapse database, there are a total of 341 research and development pipelines worldwide in the direction of this disease, with 4 drugs approved on the market, 6 projects in phase III clinical trials, 40 projects in phase II clinical trials and 45 projects in phase I clinical trials

[39]

The future of IPF treatment is seen through innovations in the integration of early and less invasive diagnosis, with biomarkers acting as important pieces, as well as research into therapies aimed at more than restricting the progression of the disease, but reversing fibrosis and, therefore, promoting the restitution of natural tissue

[3]

This project is justified by the need to reverse the IPF process. Being a disease that is difficult to treat and has a dismal prognosis, a survey of the literature on it contributes to organizing current knowledge and developing possible new treatment strategies. It also contributes to a better understanding of the reasons that can lead to fibrosis, which can affect several organs, as well as the anticipation of this propensity through research into the value of potential early biomarkers. Considering the current scenario, due to the grim prognosis and lack of cure for IPF, the importance of addressing studies that can support actions for treatment and possible cure of the disease is evident.

This work has the general objective of conducting a literature review on advances in the treatment of IPF. This review was conducted in order to seek information about potential etiologies of this disease, research current treatments and their limitations, investigate cutting-edge research in regenerative therapies, culminate in a discussion of the differences between current treatments and regenerative therapies, and to point out potential paths forward.

2. Methodology

The study involved a systematic and integrative bibliographic review using literature between January 2014 and December 2024. It comprised original scientific articles, published in scientific journals. All written in Portuguese, English, or Spanish.

Exclusion criteria were theses, monographs and dissertations, materials from non-scientific journals, articles not peer-reviewed and written in languages other than Portuguese, English or Spanish, topics outside the scope of this work and outside the chosen period.

The configuration of the results was obtained by executing three sequential steps, exemplified in Figure 1 and Figure 2. In step number 1, the research platforms were established (PubMed and Capes newspaper portal). The second step included the research terms, called determined specific descriptors, which were: Current understanding of the causes of IPF; IPF treatment modalities; Drug Research for IPF; Stem cells for the treatment of IPF. The third and final step consisted of carrying out searches and analyzing the literature.

Source: Authors

[37]	SOUZA, R. L. D; FRANCO, L. G. M. D. M; SIQUEIRA, M. C. D. General Approach to Idiopathic Pulmonary Fibrosis, Brazil, v. 23, n. 3, p. 1-7, March/2023. Available at: https://doi.org/10.25248/REAMed.e12623.2023 (Accessed on: 5 Aug. 2024). View Article
[26]	OLDHAM, Justin M; VANCHERI, Carlo. Rethinking Idiopathic Pulmonary Fibrosis. Clinics in Chest Medicine, USA, v. 42, n. 2, p. 263-273, June/2021. Available at: https://doi.org/10.1016/j.ccm.2021.03.005 View Article
[22]	MEI, Q. et al. Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis. Frontiers in Pharmacology, China, v. 19, n. 12, p. 797292, Jan./2022. Available at: https://doi.org/10.3389/fphar.2021.797292 View Article

	TITLE	YEAR	COUNTRY	AUTHORS	OBJECTIVE	RESULTS
1	Idiopathic Pulmonary Fibrosis: Review of Current Knowledge	2024	Slovakia	Muri, et al.	Presentation of ongoing stem cell trials	Mesenchymal stem cells have shown promising results; Research is underway for new options such as PRM-151, Pamrevlumab and Galectin-3
2	Pulmonary fibrosis: Is stem cell therapy the way forward?	2023	Pakistan	Ikrama, et al.	Importance of stem cells in the treatment of IPF	Stem cells: regeneration and reduction of inflammation; Challenges: costs, ethical issues and immunological compatibility.
3	Stem cell-based therapy for pulmonary fibrosis	2022	China	Wenzhao Cheng, Yiming Zeng, Dachun Wang	Combination of stem cell therapies and gene therapy	Lung transplant: The only option for terminal stages; Stem cells: therapy for lung regeneration;
4	Therapeutic Applications of Mesenchymal Stem Cells in Idiopathic Pulmonary Fibrosis	2021	China	Yang, et al.	Presentation of ongoing stem cell trials	Mesenchymal stem cell (MSC) therapy regulates immunity and promotes tissue repair
5	Mesenchymal stem cells and pulmonary fibrosis: a bibliometric and visualization analysis of literature published between 2002 and 2021	2023	China	Yang, et al.	Presentation of ongoing stem cell trials	Analysis of 1,457 publications on mesenchymal stem cells (MSCs) in the treatment of (IPF), increase in research in the area; USA led publications
6	Molecular Mechanisms of Pulmonary Fibrogenesis and Its Progression to Lung Cancer: A Review	2019	Japan	Tomonari Kinoshita, Taichiro Goto	Oncogenic panorama of IPF	Common molecular mechanisms between IPF and lung cancer;
7	The oncogenic landscape of the idiopathic pulmonary fibrosis: a narrative review	2022	Italy	Stella, et al.	Oncogenic panorama of IPF	Similarities of the molecular mechanisms of IPF with cancer; distinct dynamics; Personalized strategies.
8	Turning the tide: From fibrosis to regeneration following anti-fibrogenic cell vaccination	2022	United States of America	Ira Phadke, Alka Dwivedi, Naomi Taylor	Oncogenic panorama of IPF	Proposal for an immunotherapeutic vaccine targeting specific antigens of fibrogenic cells, such as ADAM12 in the liver and GLI1 in the lungs. Potential treatment for fibrotic diseases.
9	Lysophophatidic acid receptor 1 inhibition: a potential treatment target for pulmonary fibrosis	2024	United States of America	Volkmann et al.	Potential treatments	Investigation of ATX and LPAR1 Inhibitors as Promising Therapies in Clinical Trials for the Treatment of the Disease
10	Targeting Alveolar Repair in Idiopathic Pulmonary Fibrosis	2021	United Kingdom	Ptasinski VA, Stegmayr J, Belvisi MG, Wagner DE, Murray LA.	Potential treatments	Stem cell modulation; anti-inflammatory and antifibrotic therapies; the body's own repair capacity; promotion of tissue regeneration without stimulating the formation of pathological scars; understanding the molecular mechanisms that regulate alveolar repair; identification of therapeutic targets improving the prognosis of patients with IPF.
11	Target tumour suppressor p53 for organ fibrosis therapy	2024	China	Bao, et al.	Potential treatments	Modifying p53 activity is a promising therapeutic approach to treat IPF
12	Idiopathic pulmonary fibrosis and the role of genetics in the era of precision medicine	2023	Spain	Gonzalez, et al.	Genetic sequencing (protocol)	Explores how rare and common genetic variants influence the risk and progression of idiopathic pulmonary fibrosis (IPF). It also discusses how genomic technologies can improve diagnosis, prognosis, and genetic screening strategies for IPF.
13	The Inflammasome NLR Family Pyrin Domain-Containing Protein 3 (NLRP3) as a Novel Therapeutic Target for Idiopathic Pulmonary Fibrosis	2022	United States of America	Biancatell, et al.	Potential treatments	Reviews evidence on NLRP3 activation in idiopathic pulmonary fibrosis and highlights recent advances in direct and indirect NLRP3 inhibitors.
14	The Genetic and Epigenetic Footprint in Idiopathic Pulmonary Fibrosis and Familial Pulmonary Fibrosis: A state-of-the-Art Review	2022	Italy	Tirelli, et al.	Epigenetic factors of IPF such as biomarkers or druggable targets	Analyzes the genetic and epigenetic mechanisms involved in idiopathic pulmonary fibrosis (IPF) and familial pulmonary fibrosis (FPF). Highlights mutations in genes related to telomerase (TERT, TERC, PARN, RTEL1) and surfactant proteins (SFTPC, SFTPA1, SFTPA2, ABCA3) as well as polymorphism in the MUC5B and TOLLIP genes, which contribute to fibrogenesis. The study also addresses epigenetic alterations such as DNA methylation.
15	European Respiratory Society statement on familial pulmonary fibrosis	2022	France	Borie, et al.	Genetic sequencing (protocol)	Addresses genetic predisposition in IPF evidenced by several genetic mutations associated with the disease. The statement provides guidelines on genetic sequencing, clinical counseling, management and screening of patients with familial pulmonary fibrosis (FPF) and their family members, aiming to improve the diagnosis and treatment of this condition.
16	Genetic Risk Factors for Idiopathic Pulmonary Fibrosis: Insights into Immunopathogenesis	2020	United States of America	Jacob E Michalski, David A Schwartz	Genetic factors involved in IPF	It explores the genetic factors associated with the development of IPF and their implications in the immunopathogenesis of the disease. The authors highlight that genetic variations account for at least one third of the risk of developing IPF. Among these, the gain-of-function variant in the promoter of the MUC5B gene is indicated as the most significant risk factor, genetic or otherwise, for the disease.
17	Revealing the Pathogenic and Aging-related Mechanisms of the Enigmatic Idiopathic Pulmonary Fibrosis	2014	Mexico	Moisés Selman, Annie Pardo	Genetic variants in the aged lung	Explores the pathogenetic and age-related mechanisms of idiopathic pulmonary fibrosis (IPF). The authors propose that aberrant activation of alveolar epithelial cells and fibroblasts in aged lungs plays a crucial role in the pathogenesis of IPF
18	Precision medicine advances in idiopathic pulmonary fibrosis	2023	United States of America	Karampitsakos, et al.	Precision medicine in IPF patients	The work emphasizes that the adoption of precision medicine strategies in IPF has the potential to transform disease management but requires continued effort to integrate these scientific discoveries into daily clinical practice.
19	Molecular and Genetic Biomarkers in Idiopathic Pulmonary Fibrosis: Where Are We Now?	2023	Greck	Tomos, et al.	Epigenetic factors of IPF such as biomarkers or druggable targets	The article highlights the relevance of molecular and genetic biomarkers in understanding and managing IPF, emphasizing the need for further research to validate and implement these biomarkers in clinical practice.
20	Research progress in the molecular mechanisms, therapeutic targets, ad drugs development of Idiopathic Pulmonary Fibrosis	2022	China	Ma, et al	Genetic factors involved in IPF	This article summarizes advances in understanding the molecular mechanisms of IPF and how these discoveries are being translated into new therapeutic strategies and drug development aimed at improving management and clinical outcomes for patients.
21	Pharmacological expansion of type 2 alveolar epithelial cells promotes regenerative lower air repair	2024	United States of America	Shao, et al.	Potential treatments	This article suggests that DPP4 inhibition may be a promising strategy to stimulate lung regeneration in diseases such as idiopathic pulmonary fibrosis (IPF) offers a new therapeutic approach for degenerative lung conditions.
22	US patent covers brilaroxazine in treating IPF, like diseases	2024	United States of America	Bhat; Laxminarayan	Potential treatments	In 2024, the United States Patent and Trademark Office (USPTO) granted patent No. 12053477 to Reviva Pharmaceuticals Holdings for the use of brilaroxazine in the treatment of idiopathic pulmonary fibrosis (IPF) and other fibrosing lung diseases, including those associated with chronic obstructive pulmonary disease (COPD), sickle cell anemia, scleroderma, and lung cancer.
23	Idiopathic Pulmonary Fibrosis: Addressing the current and future therapeutic advances along with the role of Sotatercept in the management of pulmonary hypertension	2023	India	Hadi, et al.	Potential treatments	The article provides valuable insights into current and future therapeutic options for IPF, emphasizing the need for continued research to improve patient outcomes.
24	Promising advances in treatments for the management of idiopathic pulmonary fibrosis	2024	Italy	Carmelo Sofia, Alessia Comes, Giacomo Sgalla, Luca Richeldi	Potential treatments	This multifaceted approach is expected to significantly improve the overall treatment of patients with IPF, supporting optimistic expectations of reversing fibrotic changes and ultimately restoring lung function to a normal state.
25	A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models	2024	China	Feng Ren, et al.	Epigenetic factors of IPF such as biomarkers or druggable targets	A generative AI platform was used to unbiasedly identify TNIK as an antifibrotic target. TNIK has also been implicated in multiple hallmarks of aging, suggesting broader therapeutic potential
26	Exploring Therapeutic targets for molecular therapy of idiopathic pulmonary fibrosis	2024	China	Li, et al.	Genetic factors involved in IPF	It has mainly focused on therapeutic targets that have not only entered clinical trials but have also been publicly published with their clinical results. Until now, many researchers have focused on the downstream effectors of gene expression, such as cytokines and enzymes. Epigenetic modification also plays a vital role in IPF.
27	Current and Novel Treatment Modalities of Idiopathic Pulmonary Fibrosis	2024	United States of America	Mahnoor Arshad, Zoraize Moeez Athar, Tasneem Hiba	Current treatment modalities	This article provides an overview of current treatment modalities for IPF and explores the need for new therapeutic approaches.
28	The Bright side of fibroblastic: molecular signature and regenerative cues in major organs	2021	Portugal	Rita N Gomes, Filipa Manuel, Diana S Nascimento	Potential treatments	The positive side of fibroblasts: molecular signature and regenerative signals in major organs
29	Human Adipose-derived Mesenchymal Stem Cells Attenuate Early Stage of Bleomycin Induced Pulmonary Fibrosis: Comparison with Pirfenidone	2016	India	Reddy, et al.	Presentation of ongoing stem cell trials	In the present study, AD-MSCs were shown to be effective in improving the symptoms of pulmonary fibrosis, increasing survival capacity and protecting against pulmonary fibrosis comparatively better than pirfenidone.
30	Engineered Lung Tissues Prepared from Decellularized lung slices	2022	United States of America	Leiby, et al.	Precision medicine in IPF patients	In summary, this protocol describes a robust system to generate engineered lung tissues for culture studies of AEC2s, fibroblasts, and endothelial cells within acellular ECM lung slice scaffolds.
31	Early decrease in erector spinae muscle area and future risk of mortality in idiopathic pulmonary fibrosis	2020	Japan	Nakano, et al.	Epigenetic factors of IPF such as biomarkers or druggable targets	Early decrease in ESMCSA may be a useful predictor of prognosis in patients with IPF.
32	Innovative Pre-Clinical Data Using Peptides to Intervene in the Evolution of Pulmonary Fibrosis	2023	Brazil	Simon, et al.	Potential treatments	This work aimed to apply a therapeutic alternative using immunomodulatory peptides in a murine model of chronic pulmonary fibrosis.
33	Administration of Collagen Peptide Prevents the Progression of Pulmonary Fibrosis in Bleomycin-Treated Mice	2023	Japan	Yoshihara, et al.	Potential treatments	The results of this study suggest that CP (PEPTIDE COLLAGEN) supplementation prevents the development of IPF by acting as an anti-inflammatory agent.

Mediators		IPF	Lung Cancer
Abnormal mRNA	let-7	down-regulated	down-regulated
	miR-21	up-regulated	up-regulated
	miR-29	down-regulated	down-regulated
	miR-30	down-regulated	down-regulated
	miR-155	up-regulated	up-regulated
	miR-200	down-regulated	down-regulated
Cell-free DNA	-	up-regulated	up-regulated
Glycoprotein	Thy-1	down-regulated	down-regulated
Connexin	Cx43	down-regulated	down-regulated
Growth Factors	TGF-β	up-regulated	up-regulated
Growth Factors	PDGF	up-regulated	up-regulated
Migration	VEGF	up-regulated	up-regulated
	FGF	up-regulated	up-regulated
	laminin	up-regulated	up-regulated
	fascin	up-regulated	up-regulated
Pathways	heat shock protein 27	up-regulated	up-regulated
	Wnt pathway	up-regulated	up-regulated
	PI3K/Akt pathway	up-regulated	up-regulated
Immune Cells	FAM	up-regulated	up-regulated
	MDSC	up-regulated	up-regulated
	Treg	down-regulated	up-regulated

Gene ¹	Main Function	Profibrotic Mechanism
TERT	Telomerase	Decreased activity of telomerase
TERC	Reverse Transcription in Telomerase	Decreased activity of telomerase
PARN	Stability of mRNA in Telomerase	Shortening of telomeres
RTEL1	DNA helicase in Telomerase	Shortening of telomeres
SFTPA1	Modulate surface tension in the alveoli	Increased ER stress
SFTPA2	Modulate innate and adaptive immunity	Increased ER stress
SFTPC	Stabilize the surfactant fluid	Increased ER stress
ABCA3	Lipid transport across membranes	Increased ER stress and apoptosis
MUC5B	Mucin 5B production	Muco-ciliary disfunction
TOLLIP	Inhibitory adaptor protein within TLR	Decreased protection against ROS

Treatment Modality	Description
Pirfenidone	Oral medication that reduces fibroblast activity and pro-inflammatory cytokines.
Nintedanibe	Oral medication that inhibits multiple tyrosine kinases involved in fibroblast proliferation.
Oxygen Therapy	It provides supplemental oxygen to improve oxygenation and relieve symptoms of hypoxemia.
Pulmonary Rehabilitation	Comprehensive programs, including exercise training, education, and support to improve lung function and overall well-being.
Lung Transplantation	Considered for patients with advanced idiopathic pulmonary fibrosis who meet specific criteria to improve survival and quality of life.

Treatment	Mechanism of action	Clinical effects
Current therapies
Pirfenidone	Antifibrotic and anti-inflammatory	Slows rate of decline in FVC
Nintedanibe	Antifibrotic and anti-inflammatory	Slows rate of decline in FVC
Oral corticosteroids, opioids	Antitussive	Decreases cough and improves quality of life
Anti-acids, proton pump inhibitors	Decreases GERD	Benefits unclear
Lung transplantation	Surgical replacement of one or both lungs	Available only as a potentially curative therapy
Therapies in development
PRM-151	Recombinant human pentraxin-2; acts as an antifibrotic agent	Slows rate of decline in FVC
Pamrevlumab	Fully human recombinant monoclonal antibody to CTGF	Slows rate of decline in FVC
TD139	Small molecule inhibitor of galectin-3	Decreases plasma biomarkers of inflammation; study in progress to assess effect on FVC
PLN-74809	Blocks activation of the TGFβ pathway	Study in progress with end-points of safety, tolerability, and pharmacokinetics
TRK-250	Suppresses TGFβ expression	Study in progress to assess the safety and tolerability of single and multiple inhaled doses

TITLE	TARGET OR FACTOR ASSOCIATED WITH IPF IDENTIFIED	THERAPY OR MEDICATION
Lysophophatidic acid receptor 1 inhibition: a potential treatment target for pulmonary fibrosis	Lysophosphatidic acid (LPA)-mediated activation of LPA receptor 1 (LPAR1); and the LPA-producing enzyme autotaxin (ATX) and activation of LPAR1	Signaling in pulmonary fibrosis and to help differentiate new inhibitors in development
Targeting Alveolar Repair in Idiopathic Pulmonary Fibrosis	reparative epithelial progenitor cells in the alveolar region of the lung	Endogenous alveolar repair
The Bright side of fibroblastic: molecular signature and regenerative cues in major organs	The bright side of fibroblasts: molecular signature and regenerative signals in major organs: updated overview of fibroblast-derived regenerative signaling in different organs and discuss how this capacity may be compromised with aging	We also introduce a new paradigm for regenerative therapies based on the reversion of adult fibroblasts to a fetal/neonatal-like phenotype.
Target tumor suppressor p53 for organ fibrosis therapy	Tumor suppressor p53 (p53), known for its regulatory role in cell proliferation, apoptosis, aging and metabolism in various tissues	Development of strategies targeting p53 for the treatment of organ fibrosis
The Inflammasome NLR Family Pyrin Domain-Containing Protein 3 (NLRP3) as a Novel Therapeutic Target for Idiopathic Pulmonary Fibrosis	NLR family pyrin domain-containing protein 3 (NLRP3), once activated, promotes the production of IL-1β, IL-18, and innate immune responses.	Inhibition of NLRPP3 may offer a promising approach against the fibrotic process in the lungs
Pharmacological expansion of type 2 alveolar epithelial cells promotes regenerative lower air repair	Dipeptidyl peptidase 4 (DPP4) inhibitors selectively expand AEC2s (alveolar epithelial cells type 2 are stem cells in the adult lung that contribute to lower airway repair) and are broadly effective in several mouse models of lung injury.	Z-97, a persistent, locally administered pulmonary DPP4 inhibitor that broadly promotes efficacy in mouse lung injury models with minimal peripheral exposure and good tolerability.
US patent (US-12053477-B2) covers brilaroxazine in treating IPF, like diseases	Dopamine and serotonin play important roles in regulating processes such as fibrosis (scarring) and inflammation.	Brilaroxazine is a new chemical entity designed to modulate the activity of dopamine and serotonin receptors, two key signaling molecules
Idiopathic Pulmonary Fibrosis: Addressing the current and future therapeutic advances along with the role of Sotatercept in the management of pulmonary hypertension	Inhibition of several tyrosine kinases decreases the proliferative activities that lead to fibrosis.	Saracatinib is a tyrosine kinase inhibitor that primarily targets the SRC protein, potentially used to treat diseases such as pulmonary fibrosis by inhibiting fibroblast activity and collagen deposition, while Sotatercept is a fusion protein used to treat pulmonary arterial hypertension (PAH) by targeting specific pathways that contribute to abnormal blood vessel growth in the lungs;
Promising advances in treatments for the management of idiopathic pulmonary fibrosis	Presents a collection of phase 3 tests: Targets: PDe4B; Fibroblast activities; CTGF; Innate immune response; Lung microbiome	"BI 1,015,550; Inhaled treprostinil; Pamrevlumab
Innovative Pre-Clinical Data Using Peptides to Intervene in the Evolution of Pulmonary Fibrosis	Immunomodulatory peptides ToAP3 and ToAP4	Immunomodulatory peptides ToAP3 and ToAP4: both peptides controlled experimental IPF, maintaining tissue characteristics and standard functional properties and regulating the production of cytokines associated with fibrosis. The data obtained in this work show that the regulation of the immune response by ToAP3 and ToAP4 can control the alterations that cause the fibrotic process, making both peptides potential therapeutic alternatives and/or adjuvants for IPF.
Administration of Collagen Peptide Prevents the Progression of Pulmonary Fibrosis in Bleomycin-Treated Mice	Peptide collagen	The present study showed that administration of peptide collagen derived from chicken feet suppressed the progression of Pulmonary Fibrosis in mice.
Exploring Therapeutic targets for molecular therapy of idiopathic pulmonary fibrosis	Transforming growth factor beta, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, lysophosphatidic acid, interleukin-13, Rho-associated coiled-coil forming protein kinase family, and Janus kinases/signal transducers and activators of transcription pathway.	Transforming growth factor beta, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, lysophosphatidic acid, interleukin-13, Rho-associated coiled-coil forming protein kinase family, and Janus kinases/signal transducers and activators of transcription pathway.
Turning the tide: From fibrosis to regeneration following anti-fibrogenic cell vaccination	ADAM12, a member of the A Disintegrin and Metalloprotease (ADAM) family of proteins that harbors extracellular metalloprotease and intracellular signaling properties. ADAM12 is an interesting target because tissue-resident ADAM12+ cells have been identified as the source of most a-SMA+ myofibroblasts generated after acute muscle and dermal injury, and its expression is largely limited to the embryonic period. GLI1 is expressed in mesenchymal cells after injury, giving rise to a-SMA+ myofibroblasts after tissue injury	Novel immunotherapeutic vaccine approach to target fibrotic lesions in models of liver and lung fibrosis: (This therapeutic strategy is similar to a cancer vaccine approach, but instead of targeting tumor-specific antigens, it targets fibrogenic cell-specific antigens.) Vaccination with a lentiviral vector encoding Gli1 abrogates bleomycin-induced lung fibrosis
A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models	It was identified TRAF2- and NCK-interacting kinase (TNIK) as an antifibrotic target using a predictive artificial intelligence (AI) approach.	"INS018_055, a small molecule TNIK inhibitor, was generated, which exhibits desirable drug-like properties and antifibrotic activity in different organs in vivo via oral, inhaled or topical administration. INS018_055 possesses anti-inflammatory effects in addition to its antifibrotic profile, validated in multiple in vivo studies.

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Target molecule	Drug or treatment	Administration route	Clinical trial stage	Research type	Patients number	Outcomes
galectin-3	TD139, a galectin-3 inhibitor	Inhalation, 0.3, 3, or 10 mg for 14 days	I/IIa	Double blinded, Randomized	24 patients. Each cohort: TD139 (n = 5) or placebo (n = 3)	Inhibition of Gal-3 expression in the lung was associated with reductions in plasma biomarkers (TD139 groups compared with placebo).
αvβ6 integrin	BG00011, a humanized monoclonal antibody against αvβ6 integrin	Subcutaneous, 56 mg once weekly	IIb	Double blinded, Randomized	106 patients. BG00011 (n = 54) or placebo (n = 52)	No significant difference in FVC change from baseline between patients who received BG00011 or placebo at week 26.
CTGF	Pamrevlumab, a recombinant human antibody that binds to CTGF	Intravenous, 30 mg/kg, every 3 weeks over 48 weeks	III	Double blinded, Randomized	356 patients.	Study did not meet its primary endpoint.
LPA receptor	BMS-986020 (Bristol-Myers Squibb), an antagonist of the lysophosphatidic acid (LPA) receptor 1 (LPA1)	Oral, 600 mg, once/twice daily for 26 weeks	II	Double blinded, Randomized	143 patients. placebo (n = 47), 600 mg qd (n = 48), 600 mg bid (n = 48)	Patients treated with BMS-986020 experienced a significantly slower rate of decline vs placebo in FVC at week 26.
Autotaxin (the primary enzyme responsible for the production of LPA)	GLPG1690 (Galapagos, Mechelen, Belgium), a selective inhibitor of autotaxin	Oral, 600 mg/200 mg once daily for at least 52 weeks	III	Double blinded, Randomized	1306 patients.	GLPG1690 did not improve clinical outcomes compared with placebo.
IL-13	Lebrikizumab, a monoclonal antibody inhibits the secretion of IL-13	Subcutaneous, 250 mg, every 4 weeks	II	Double blinded, Randomized	505 patients. In cohort A, 154 patients, lebrikizumab (n = 78) or placebo (n = 76). In cohort B, 351 patients received pirfenidone, lebrikizumab (n = 174) or placebo (n = 177)	The predicted decline of the annualized rate of FVC% was not met.
IL-4 and IL-13	SAR156597, a monoclonal antibody targeting IL-4 and IL-13	Subcutaneous, 200 mg once a week or once every 2 weeks	IIb	Double blinded, Randomized	325 patients, placebo (n = 109), SAR156597 Q2W (n = 108), SAR156597 QW (n = 108)	SAR156597 failed to demonstrate benefit in treating IPF patients.
Rho-associated protein kinase 2 (ROCK2)	KD025 (or SLX-2119; Kadmon Corporation, Belumosudil), a selective ROCK2 inhibitor	Oral, 400 mg once a week	II	Open-label, Randomized	76 patients. KD025 (n = 52) or best supportive care (n = 24)	KD025 reduced the decline of FVC by 73% versus patients receiving supportive care at week 24.

Pulmonary disease marker	Findings in screening asymptomatic relatives	Remarks from Task Force
Physical examination, symptoms
Dyspnea/MRC-5	May be present; not predictive for pre-clinical pulmonary fibrosis
Frequent cough	May be present; not predictive for pre-clinical pulmonary fibrosis
Clubbing	May be present
Inspiratory crackles	May be present
Pulmonary function		Can be performed in subjects from age 6 years onward
FVC	Below normal values rare
D_LCO	Below normal values may be present; lower in subjects with ILD changes than without ILD changes on HRCT
TLC	Below normal values rare; lower in subjects with ILD changes than without ILD changes on HRCT
Radiology HRCT	14–25% have ILD changes on HRCT or a diagnosis of ILD on first screening visit	One-third of SFTPA1/SFTPA2 mutation carriers may develop lung cancer
Genetic sequencing	Disease-causing variants in TRGs and SRGs	In families with a (likely) pathogenic SRG mutation: family members without the mutation are not at increased risk for FPF; in families with a (likely) pathogenic TRG mutation: family members without the mutation may have inherited short telomeres and may be at risk of development of STS
Extrapulmonary signs and symptoms of STS		In all families with unknown cause or TRG mutation
Hematological markers	Mean corpuscular volume above normal; red blood cells or platelets below normal	Abnormalities in one or several hematological cell lines are a sign of marrow dysfunction in asymptomatic carriers of TRG mutations
Liver enzymes	Elevated liver enzymes	Abnormalities in liver enzymes are a sign of hepatic disease in asymptomatic carriers of TRG mutations
Hair greying	Before 30 years of age	No consensual definition
Telomere length	<10th percentile	Low values for age associate with marrow dysfunction in asymptomatic carriers of TRG mutations

Biomarker	Pathogenetic Process	Diagnostic	Prognostic	Specimen-
S100A4	Fibrogenesis	++	++	Serum BALF Lung tissue
cCK-18	AECs apoptosis	+	-	Serum
KL-6	Alveolar epithelial marker	+	+++	Blood BALF
YKL-40	Adhesion molecule	-	++	Blood BALF Lung tissue
MMP-7	Extracellular remodelling	++	+++	Blood BALF Lung tissue
ICAM1	Adhesion molecule	-	++	Serum Blood
SPA & SPD	Alveolar epithelial markers	-	++	Serum
LOXL2	Extracellular matrix remodelling Fibrogenesis	-	+	Serum Lung tissue
Periostin	Extracellular matrix remodelling Fibrogenesis	-	+	Serum Lung tissue
CCL-18	Alternative alveolar macrophage activation	-	+	Serum BALF
IL-8	Potent chemotactic activity for polymorphonuclear leukocytes	-	+	Blood BALF
OPN	Inflammation Fibroblast migration and proliferation	-	+	Serum BALF Lung tissue
LC3β	Autophagy	-	+	Lung Tissue
BiP, XBP1	Unfolded protein response	-	+	Lung Tissue

IPF	Idiopathic Pulmonary Fibrosis
REC	Research Ethics Committee
FPF	Familial Pulmonary Fibrosis
ESCs	Embryonic Stem Cells
iPSCs	Induced Pluripotent Stem Cells
MSCs	Mesenchymal Stem Cells
EHC	Specialized Health Centers
ILD	Interstitial Lung Disease

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