Pulmonary fibrosis (PF) has a complex history, with its understanding evolving significantly over the past century. Initially, the term “pulmonary fibrosis” was used to describe various lung diseases characterized by scarring of lung tissue. The most common form, idiopathic pulmonary fibrosis (IPF), was first recognized in the 1960s, although its symptoms had been documented earlier. The Pulmonary Fibrosis Foundation (PFF) was established in 2000 by the Rosenzweig brothers, motivated by personal loss to the disease. This marked a pivotal moment in advocacy and research, leading to increased awareness and funding for PF research.

Over the years, significant advancements have been made in understanding the disease’s pathophysiology, with a focus on the role of inflammation and fibrosis in lung tissue. The introduction of antifibrotic medications like pirfenidone and nintedanib in the 2010s represented a breakthrough in treatment, providing options to slow disease progression.

As of 2025, pulmonary fibrosis affects over 250,000 individuals in the United States alone, with a growing prevalence worldwide. The disease is characterized by progressive scarring of lung tissue, leading to severe respiratory issues and a median survival rate of 3 to 5 years post-diagnosis. Current treatment strategies focus on managing symptoms and slowing progression, as there is no cure. The landscape of PF treatment is rapidly evolving, with more than 100 therapies currently in development globally, indicating a robust pipeline aimed at addressing this challenging condition.

Key points

• Emerging evidence for nutraceuticals: Research suggests that certain nutraceuticals, such as EGCG, quercetin, and resveratrol, may help mitigate pulmonary fibrosis symptoms by targeting inflammation, oxidative stress, and fibrotic pathways, though human studies are limited and results vary.
• Preclinical promise with human gaps: Animal models indicate potential antifibrotic effects for supplements like melatonin and astragaloside IV, but clinical trials in humans are sparse, and benefits are not yet conclusively proven.
• Safety and dosage considerations: Most of these compounds appear safe at moderate doses based on available data, but interactions and long-term effects remain understudied, especially in patients with pulmonary fibrosis.
• Holistic approach recommended: While evidence leans toward supportive roles in reducing fibrosis progression, nutraceuticals should complement, not replace, standard treatments like antifibrotic drugs, and consultation with healthcare providers is essential due to individual variability.
• Ongoing research needed: The field shows promise but highlights controversies around efficacy, with some studies reporting trends rather than definitive improvements; larger, well-designed trials could clarify their therapeutic potential.

Overview of pulmonary fibrosis and nutraceutical interventions

Pulmonary fibrosis is a progressive lung disease involving scarring that impairs breathing, often idiopathic (IPF) or linked to environmental factors. Standard treatments slow progression but don’t reverse damage. Nutraceuticals—natural compounds with health benefits—offer potential adjunctive support by addressing underlying mechanisms like inflammation and collagen buildup. This review focuses on 10 selected supplements, drawing from preclinical and limited human data.

Potential mechanisms and benefits

These nutraceuticals primarily act as antioxidants, anti-inflammatories, or modulators of fibrotic signaling (e.g., TGF-β pathways). For instance, EGCG from green tea may inhibit collagen cross-linking, while omega-3 fatty acids correlate with better lung function in observational studies. Benefits could include reduced symptom severity and slower disease advancement, but effects are context-dependent and not universal.

Limitations and future directions

Evidence is mostly from animal models, with human trials small-scale or observational. While promising, results are not absolute, and factors like bioavailability vary. Future research should prioritize randomized controlled trials to validate these approaches.

Abstract

Pulmonary fibrosis (PF), including idiopathic pulmonary fibrosis (IPF), is a chronic, progressive interstitial lung disease characterized by excessive extracellular matrix deposition, leading to irreversible lung scarring and impaired respiratory function. Current pharmacological therapies, such as nintedanib and pirfenidone, slow disease progression but offer limited reversal of established fibrosis. Nutraceuticals, derived from natural sources, have garnered attention for their potential antifibrotic, anti-inflammatory, and antioxidant properties. This review synthesizes preclinical and clinical evidence on 10 selected nutraceuticals—EGCG (epigallocatechin gallate from green tea), quercetin, omega-3 fatty acids, resveratrol, melatonin, astragaloside IV (from Astragalus root), neferine (from lotus seed), andrographolide (from Andrographis paniculata), cordycepin (from Cordyceps sinensis mushroom), and fucoidan (from brown seaweed)—in combating PF. Drawing from animal models (e.g., bleomycin-induced PF) and limited human studies, we discuss mechanisms such as TGF-β inhibition, Nrf2 activation, and senescence clearance. While promising, human data remain preliminary, emphasizing the need for larger trials to establish efficacy and safety.

Introduction

Pulmonary fibrosis encompasses a group of disorders marked by fibroblast activation, epithelial-mesenchymal transition (EMT), and collagen accumulation, often triggered by environmental insults like bleomycin (BLM), silica, or radiation. IPF, the most common form, affects over 3 million people globally and carries a poor prognosis, with median survival of 3-5 years post-diagnosis. Pathophysiological hallmarks include dysregulated TGF-β signaling, oxidative stress, inflammasome activation, and cellular senescence. Nutraceuticals offer a complementary strategy, potentially modulating these pathways with fewer side effects than conventional drugs. This paper reviews evidence for the specified compounds, integrating user-provided insights with recent literature, focusing on published studies.

EGCG (Epigallocatechin Gallate from green tea)

EGCG, a polyphenol abundant in green tea, exhibits antifibrotic potential through inhibition of lysyl oxidase-like 2 (LOXL2) and TGF-β1 signaling, reducing collagen cross-linking. A small human study (n=10 IPF patients) demonstrated oral EGCG (400-1200 mg/day) reversed TGF-β1-driven profibrotic markers in lung biopsies after 14 days. Ongoing Phase I trials evaluate safety and dosing, with doses up to 800 mg/day deemed safe. Preclinically, EGCG attenuates BLM-induced PF in mice via Nrf2 activation, promoting epithelial regeneration.

Additional research supports these findings. For example, a 2019 study using next-generation sequencing showed EGCG alters gene expression in IPF fibroblasts, reducing oxidative and fibrotic responses.¹ In precision-cut lung slices from IPF patients, EGCG induced collagen turnover by blocking LOXL2 and TGF-β1 receptor kinase.² A 2024 study highlighted EGCG’s role in reducing secreted frizzled-related protein 2 (sFRP2) near alveolar epithelial cells, mitigating EMT.³ However, interactions with drugs like nintedanib warrant caution, as EGCG may alter bioavailability.⁴ Derivatives like ABI-171 show enhanced efficacy in BLM mouse models.⁵

Quercetin

Quercetin, a flavonoid with antioxidant and senolytic properties, targets senescence-associated secretory phenotype (SASP) in fibrotic lungs. Pilot human trials (n=14-20 IPF patients) using dasatinib + quercetin demonstrated safety, reduced frailty, and senescence burden, though pooled analyses showed no major functional gains.^6,7 Preclinically, it reduces senescence and fibrosis in BLM/silica models, reversing EMT and collagen deposition (equivalent to 500 mg/day human dose). Bioavailability improves with piperine.

Human studies include a 2023 Phase I trial confirming tolerability in IPF patients.⁶ A 2019 open-label pilot reported physical function improvements.⁷ Mechanistically, quercetin clears senescent fibroblasts, as shown in a 2017 study.⁸ A 2025 review discusses its gene regulatory roles in IPF comorbidities.⁹ In mice, it inhibits macrophage senescence in silica-induced PF.¹⁰

Omega-3 fatty acids

Omega-3 fatty acids (e.g., EPA, DHA) exert anti-inflammatory effects, potentially slowing PF progression. Observational data from over 300 IPF patients link higher plasma levels to improved forced vital capacity (FVC), slower decline, and longer transplant-free survival. No direct IPF trials exist, but preclinical evidence supports lung injury protection.

A 2024 study associated higher omega-3 levels with better PF outcomes.¹¹ In cystic fibrosis (CF), related to fibrotic lung changes, supplementation improved pulmonary function.¹² A 2016 pilot in CF patients showed enhanced exercise tolerance after 1 year.¹³ An 8-month CF trial reported fatty acid profile shifts and clinical benefits.¹⁴ Symposium data from 2016 noted PF patient outcomes, indirectly supporting anti-inflammatory roles.¹⁵

Resveratrol

Resveratrol activates SIRT1, promoting myofibroblast apoptosis and reducing ECM via NF-κB inhibition. Multiple animal studies (BLM/RA-ILD models) show fibrosis attenuation, with 50% collagen reduction and improved survival. Polydatin enhances bioavailability (3-4x). Human trials (150-500 mg/day) improve endothelial function; synergy with polydatin in peritoneal fibrosis suggests lung potential.

In a 2023 study, resveratrol mitigated diesel exhaust-induced PF in mice via SIRT1/FoxO3.¹⁶ BLM rat models showed alleviation via HIF-1α/NF-κB suppression.¹⁷ It inhibits miR-21 through MAPK/AP-1.¹⁸ TGF-β/Smad/ERK modulation was evident in 2023 research.¹⁹ EMT downregulation via TLR4/NF-κB and TGF-β1/Smad3 occurred in rats.²⁰

Melatonin

Melatonin, with antioxidant properties, prevents fibrosis via Hippo/YAP1 and EMT inhibition in BLM/PM2.5 models, improving mitochondrial function. Strong preclinical evidence shows attenuation and partial reversal of established PF.

A 2023 mouse study showed NRF2 activation and galectin-3 inhibition.²¹ In 2002, it reduced BLM-induced fibrosis in rats.²² ER stress and EMT were inhibited in 2014 mouse models.²³ COX-2 modulation alleviated BLM effects in 2015.²⁴ PM2.5-induced PF was prevented in 2024 via EMT targeting.²⁵

Astragaloside IV (from Astragalus Root)

Astragaloside IV regenerates via PTEN/PI3K inhibition and stem cell mobilization. A meta-analysis of 10 animal studies (n=142) showed significant PF score reversal (SMD -2.5) in BLM/silica models (20-80 mg/kg). Safe in TCM for lung conditions, it promotes epithelial repair.

A 2025 meta-analysis confirmed therapeutic effects.²⁶ In COPD-related PF, it targeted RAS/RAF/FoxO.²⁷ Circ_0008898/miR-211-5p/HMGB1 axis was restrained in 2024.²⁸ Synergy with ferulic acid modulated TGF-β1/Smad3.²⁹ LncRNA-ATB/miR-200c/ZEB1 inhibited EMT.³⁰

Neferine (Bisbenzylisoquinoline alkaloid from Lotus Seed)

Neferine reverses EMT via TGF-β suppression, attenuating BLM/amiodarone-induced PF in rats, restoring SOD and reducing MDA (10-40 mg/kg). Human anti-inflammatory effects suggest lung regeneration via apoptosis.

A 2010 study attenuated BLM-induced PF.³¹ Protective against amiodarone in 2013 mice.³² Inhibited hepatic stellate cells, relevant to PF.³³ Pharmacokinetics with amiodarone in 2011.³⁴ Inhibited activation via TGF-β1/Smads/ERK in 2023.³⁵

Andrographolide (from Andrographis paniculata)

Andrographolide inhibits NLRP3 inflammasome and pyroptosis, ameliorating silica/BLM PF (5-20 mg/kg). Radiation models show repair; safe in human respiratory trials (60-180 mg/day).

A 2018 study ameliorated silica PF in mice.³⁶ Protective in BLM mice in 2013.³⁷ Suppressed proliferation via TGF-β1/Smad in 2020.³⁸ Improved MMP-1/TIMP-1 in 2015.³⁹ Reduced cytokines in BLM rats in 2011.⁴⁰

Cordycepin (from Cordyceps sinensis mushroom)

Cordycepin reverses EMT and mitochondrial stress, alleviating IPF in mice via mitochondrion protection (10-50 mg/kg). A 2024 study reduced collagen; TCM uses for lung tonifying, safe in fatigue trials.

A 2012 study protected against lung fibrosis in rats.⁴¹ Ion transport effects in 2008 airway cells.⁴²

Fucoidan (Sulfated Polysaccharide from brown seaweed)

Fucoidan activates Nrf2, degrading ECM in BLM/radiation models (50-100 mg/kg low-MW forms reduce 30-50% fibrosis). Safe in human inflammation trials (1-3 g/day).

A 2023 study isolated fucoidan with anti-IPF activity.⁴³ LMWF inhibited via antioxidants in 2022.⁴⁴ Attenuated EMT in 2021.⁴⁵ Inhibited TGF-β1 via ERK in 2019.⁴⁶ Lung function benefits in viral infections in 2020.⁴⁷

Summary of evidence levels and mechanisms

Discussion

These nutraceuticals target overlapping pathways, suggesting synergistic potential (e.g., EGCG with resveratrol). However, human evidence is limited to small pilots or observational data, with preclinical dominance. Bioavailability challenges (e.g., resveratrol) necessitate formulations like polydatin. Safety profiles are favorable, but drug interactions (e.g., EGCG with nintedanib) require monitoring.

Conclusion

Nutraceuticals offer promising adjunctive strategies for PF, potentially reversing markers via anti-fibrotic mechanisms. Larger RCTs are essential to translate preclinical findings.

Key citations

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