Fibrosis

Fibrosis is one of the most universal biological mechanisms in human disease. It links conditions as different as idiopathic pulmonary fibrosis, hepatic cirrhosis, chronic kidney disease, post-infarction heart failure, systemic sclerosis, Dupuytren's contracture and Peyronie's disease. Understanding fibrosis means understanding how normal wound healing, when repeated or unresolved, tips over into pathological scarring.

This dossier is written for patients, caregivers and healthcare professionals looking for a clear, neutral, evidence-based overview of what fibrosis is, why it develops, which organs it affects and what current medicine can — and cannot — do about it. It is not restricted to pulmonary fibrosis: the goal is a broad, organ-agnostic view of fibrotic biology.

• Fibrosis is the excessive, persistent accumulation of extracellular matrix — mostly collagen — that stiffens tissue and impairs its function.
• It is not a disease by itself: fibrosis is a shared mechanism underlying many chronic conditions in the lung, liver, heart, kidney, skin, penis and hand.
• At the cellular level, fibroblasts differentiate into contractile myofibroblasts under TGF-β1, deposit type I/III collagen and resist turnover by MMPs.
• Early fibrosis can partially regress if the underlying cause is treated; mature, cross-linked fibrosis is difficult to reverse and progression can only be slowed.
• Two antifibrotic drugs (pirfenidone, nintedanib) are approved in idiopathic pulmonary fibrosis. Renin-angiotensin blockade is established in kidney and cardiac fibrosis.

Fibrosis is the excessive, persistent accumulation of extracellular matrix — mostly type I collagen — in a tissue, in response to repeated or unresolved injury. It replaces functional parenchyma with scar-like tissue, stiffens the organ and impairs its function.

Unlike a benign scar left after a single wound heals, fibrosis is a dynamic and self-sustaining process. Activated fibroblasts differentiate into contractile myofibroblasts, deposit cross-linked collagen and resist normal turnover by matrix metalloproteinases (MMPs). Over time, the affected tissue becomes stiffer, less vascularised and progressively unable to perform its specialised functions — gas exchange in the lung, filtration in the kidney, contraction in the heart, storage and detoxification in the liver.

Fibrosis is not a disease by itself: it is a shared mechanism that manifests as many distinct clinical conditions depending on where it occurs.

Fibrosis develops when a tissue is injured repeatedly or when repair signalling fails to switch off after normal wound healing. Under those conditions, fibroblasts remain activated as myofibroblasts and continue depositing collagen long after the initial injury.

Almost every fibrotic disease follows the same overall sequence:

1. Injury to the parenchyma (viral, toxic, metabolic, ischaemic, autoimmune or mechanical).
2. Inflammation with recruitment of neutrophils, monocytes and lymphocytes; release of cytokines and reactive oxygen species.
3. Repair phase: fibroblasts are activated, proliferate and secrete a provisional matrix.
4. Resolution in normal healing: myofibroblasts undergo apoptosis and the matrix is remodelled into functional tissue.
5. Persistent activation in fibrosis: myofibroblasts do not disappear, collagen deposition continues and the tissue stiffens.

Normal wound healing and fibrosis share the same actors — fibroblasts, myofibroblasts, TGF-β, collagen — but differ in duration and in the ability of the tissue to switch repair off.

For a detailed view of the physiological repair process, see our dossier on normal wound healing.

Virtually any organ can develop fibrosis. The clinical presentation, natural history and treatment depend on the organ, but the underlying cellular mechanism is largely conserved: fibroblast activation, TGF-β1 signalling, myofibroblast persistence and excess collagen deposition.

Liver fibrosis is the accumulation of extracellular matrix in the hepatic parenchyma in response to chronic injury. Its most advanced form, cirrhosis, distorts liver architecture and leads to portal hypertension and hepatocellular carcinoma risk.

The main effectors are hepatic stellate cells, which transdifferentiate into myofibroblasts under TGF-β1 and PDGF. Common causes include viral hepatitis (HBV, HCV), alcohol, non-alcoholic steatohepatitis (NASH), autoimmune hepatitis and biliary diseases. Non-invasive tools (FibroScan elastography, FIB-4, APRI) increasingly replace biopsy for staging.

Pulmonary fibrosis is the fibrotic remodelling of the lung interstitium, most typically illustrated by idiopathic pulmonary fibrosis (IPF). It is a progressive disease with a median survival of 3–5 years without treatment.

Repeated micro-injuries to the alveolar epithelium, an aberrant repair response and peri-alveolar fibroblast activation drive collagen deposition in the lung interstitium. Pirfenidone and nintedanib, the first approved antifibrotics, slow the decline of forced vital capacity without curing the disease. Pulmonary fibrosis is one example of a fibrotic disease — this dossier remains focused on the general biology of fibrosis rather than on IPF specifically.

Cardiac fibrosis is the excess deposition of collagen in the myocardial interstitium. It reduces ventricular compliance, impairs diastolic and systolic function and predisposes to arrhythmias and heart failure.

Two forms coexist: reparative fibrosis replacing cardiomyocytes lost after infarction, and reactive interstitial fibrosis driven by chronic pressure or volume overload, angiotensin II and aldosterone. Renin-angiotensin blockade (ACE inhibitors, ARBs) and mineralocorticoid antagonists reduce fibrosis and improve outcomes in heart failure.

Renal fibrosis — interstitial fibrosis and tubular atrophy (IFTA) — is the final common pathway of chronic kidney disease (CKD), regardless of the initial cause.

Persistent tubular injury, hypoxia and angiotensin II signalling drive interstitial ECM deposition, capillary rarefaction and progressive loss of glomerular filtration rate. ACE inhibitors and ARBs remain the cornerstone of nephroprotection; SGLT2 inhibitors have shown additional benefit in diabetic and non-diabetic CKD.

Skin fibrosis groups several distinct entities — systemic sclerosis (scleroderma), hypertrophic scars, keloids and localised morphea — sharing dermal fibroblast activation and excess collagen deposition.

Systemic sclerosis is an autoimmune disease with vasculopathy and fibrosis of the skin and internal organs (lung, kidney, heart, gastrointestinal tract). Biological therapies such as rituximab and tocilizumab have shown benefit in skin and lung outcomes in randomised trials.

Penile fibrosis is best represented by Peyronie's disease, a localised fibroproliferative disorder of the tunica albuginea. A fibrous plaque develops, causing curvature, painful erection and, in advanced forms, erectile dysfunction.

Peyronie's disease shares its cellular biology with other fibroses: TGF-β1, myofibroblasts and excess type I collagen. It illustrates how localised fibrosis can profoundly affect quality of life without threatening survival. For a full clinical dossier, see Peyronie's disease.

Dupuytren's contracture is a fibroproliferative disease of the palmar aponeurosis. Firm nodules and fibrous cords develop in the palm and can slowly bend one or more fingers into a fixed flexion.

Like Peyronie's disease, it involves myofibroblasts producing excess collagen; the two conditions coexist in 10–20% of patients. Read the full dossier on Dupuytren's contracture.

Early fibrosis retains some capacity for remodelling: if the injury stops (for example after antiviral cure of HCV, alcohol cessation or weight loss in NASH), part of the extracellular matrix can be degraded and the tissue partially reorganised. Once fibrosis matures, however, cross-linked collagen becomes resistant to normal turnover.

The extracellular matrix (ECM) is the three-dimensional network of proteins and polysaccharides that surrounds cells. It provides mechanical support, guides cell behaviour and stores growth factors. In fibrosis, its composition and organisation become pathological.

• Collagens I and III — major fibrillar collagens; the ratio and cross-linking pattern change in fibrosis.
• Collagen IV — basement membranes; disorganisation contributes to loss of tissue architecture.
• Fibronectin (EDA+ isoform) — pro-fibrotic matrix guiding collagen deposition.
• Elastin — provides elasticity; degraded by elastases in chronic remodelling.
• Proteoglycans (decorin, biglycan) — regulate fibrillogenesis and sequester TGF-β.
• Lysyl oxidases (LOX/LOXL2) — enzymes that cross-link collagen and stiffen the matrix.

For a dedicated dossier, see extracellular matrix.

Collagen is the most abundant protein in the human body and the main structural component of fibrotic tissue. In fibrosis, its synthesis, cross-linking and degradation are all disrupted.

Collagen turnover is normally balanced by matrix metalloproteinases (MMPs), which degrade collagen, and their inhibitors TIMPs. In fibrosis, TIMPs are upregulated and MMP activity is suppressed, tilting the balance toward net collagen accumulation. LOX-mediated cross-linking then locks the collagen fibres, making them resistant to further degradation.

Myofibroblasts are the main effector cells of fibrosis. They are activated fibroblasts that express α-smooth muscle actin (α-SMA), contain contractile stress fibres and massively produce collagen.

In normal wound healing, myofibroblasts appear briefly during the proliferative phase and undergo apoptosis at the end of repair. In fibrosis, they persist — because of continued TGF-β signalling, mechanotransduction from a stiffening matrix and senescence-driven resistance to apoptosis. They can arise from resident fibroblasts, pericytes, hepatic stellate cells or, more rarely, from epithelial or endothelial cells through EMT/EndMT.

Transforming growth factor beta 1 (TGF-β1) is the master pro-fibrotic cytokine. It drives fibroblast-to-myofibroblast differentiation, stimulates collagen synthesis and inhibits its degradation by MMPs.

TGF-β1 signals through SMAD2/3 → SMAD4 transcription factors and interacts with mechanotransduction (YAP/TAZ) and integrin-mediated pathways. Fibrotic matrix itself sequesters and re-releases TGF-β, creating a self-amplifying loop. Selective targeting of TGF-β signalling is a central goal of antifibrotic drug development, but complete blockade causes immunological side effects because TGF-β also has essential physiological roles.

Chronic, low-grade inflammation is the soil in which fibrosis grows. Neutrophils, macrophages and lymphocytes release cytokines and reactive oxygen species that sustain fibroblast activation.

Alternatively activated (M2) macrophages secrete TGF-β1, PDGF and IL-10, favouring a pro-fibrotic environment. Th2 cytokines (IL-4, IL-13) and Th17 (IL-17) contribute to fibrosis in several experimental and clinical settings. Resolution of inflammation is itself an active process; failure of resolution is a hallmark of the progression from acute injury to chronic fibrosis.

Oxidative stress — the excess of reactive oxygen species over antioxidant defences — is a well-established amplifier of fibrosis. ROS can activate latent TGF-β1, promote fibroblast-to-myofibroblast transition and inhibit MMP-mediated collagen degradation.

For a dedicated dossier on the biology of ROS, antioxidant defences and redox signalling in tissue remodelling, see oxidative stress. Chronic ischaemia, mitochondrial dysfunction and inflammation are the main sources of ROS in fibrotic tissues.

Risk factors for fibrosis are largely organ-specific but share several common denominators — chronic tissue injury, unresolved inflammation, genetic predisposition and ageing.

• Chronic infections (HBV, HCV, schistosomiasis).
• Metabolic factors (obesity, insulin resistance, NASH, diabetes).
• Toxins (alcohol, tobacco, silica, asbestos, certain drugs).
• Autoimmune diseases (systemic sclerosis, IgG4-related disease).
• Mechanical / haemodynamic stress (hypertension, pressure overload).
• Radiotherapy and repeated surgical trauma.
• Genetic variants (e.g. MUC5B in IPF, Wnt pathway in Dupuytren's).
• Ageing, through cellular senescence and impaired repair.

There is no single universal test for fibrosis. Diagnosis combines clinical assessment, blood biomarkers, imaging and, when necessary, biopsy. Strategies are organ-specific.

The most effective treatment of fibrosis is to remove the underlying cause: antiviral therapy in viral hepatitis, alcohol cessation, weight loss in NASH, blood-pressure control, immunosuppression in autoimmune diseases. On top of aetiological treatment, a small but growing number of drugs directly target fibrotic pathways.

Dietary supplements are not a validated antifibrotic treatment. Some antioxidant molecules are studied for their potential role in oxidative stress and fibroblast biology, but clinical evidence in fibrotic diseases is limited or absent.

Antifibrotic research has expanded rapidly in the last decade, moving beyond broad TGF-β blockade toward more selective, better-tolerated targets. Most programmes remain at experimental or early clinical stages.

1. Research

   Selective TGF-β targeting

   Isoform-specific or downstream (SMAD3) inhibition to avoid the immunological side effects of pan-TGF-β blockade.

2. Research

   Mechanotransduction inhibitors

   YAP/TAZ, ROCK and integrin pathways, which translate matrix stiffness into pro-fibrotic gene expression.

3. Research

   Senolytic strategies

   Elimination of senescent fibroblasts whose SASP sustains fibrosis in idiopathic pulmonary fibrosis and age-related skin fibrosis.

4. Research

   Metabolic reprogramming

   Targeting glycolysis and fatty-acid oxidation in activated myofibroblasts.

5. Research

   MicroRNA modulation

   miR-21, miR-29 and let-7 as pro- or anti-fibrotic biomarkers and therapeutic targets.

6. Research

   Cell therapies

   Mesenchymal stromal cells and derived exosomes — largely preclinical for most indications.

7. Research

   Digital pathology and AI

   Automated quantification of collagen area, fibre orientation and biopsy scoring.

No nutrient or dietary supplement has a marketing authorisation as an antifibrotic. Several nutritional approaches are nonetheless studied for their potential effect on mechanisms upstream of fibrosis — inflammation, oxidative stress, glycation — without being able to claim a direct antifibrotic effect in the regulatory sense.

• Mediterranean diet — reduction of systemic inflammation; documented benefit in cardiovascular prevention and non-alcoholic steatohepatitis (NASH).
• Omega-3 fatty acids (EPA/DHA) — modulatory effects on inflammation; preclinical data in cardiac and hepatic fibrosis.
• Vitamin D — immunomodulatory role; epidemiological associations with hepatic and pulmonary fibrosis, causality not demonstrated.
• Polyphenols — curcumin, resveratrol, quercetin, catechins: documented anti-inflammatory and antioxidant mechanisms; clinical antifibrotic effects remain limited.
• Coenzyme Q10 — mitochondrial cofactor investigated in the context of cellular ageing and oxidative stress.
• Zinc, selenium — cofactors of antioxidant enzymes (EFSA-authorised claim: "contributes to the protection of cells from oxidative stress").
• Ginkgo biloba, Boswellia serrata — extracts studied for microcirculation and inflammatory pathways; preclinical to moderate levels of evidence.

These leads are exploratory and in no case replace medical treatment of fibrosis. Dedicated dossiers for each of these ingredients will be progressively published in the Science Hub.

Nutritional approaches applied specifically to fibroproliferative diseases (Peyronie's, Dupuytren's) are analysed in detail, with their levels of evidence, in our dossier natural approaches and fibroproliferative diseases.

A selection of reference publications and international resources used to write this dossier. The list is not exhaustive and will be enriched as the dossier is updated.

Fibrosis is a universal biological mechanism that turns normal wound healing into pathological scarring when injury becomes chronic. Its cellular language — TGF-β1, myofibroblasts, cross-linked collagen — is largely conserved across organs, from the lung to the kidney and from the heart to the penis and the hand.

AARO LAB focuses on the biological mechanisms involved in fibrosis, oxidative stress and tissue integrity. Dietary supplements are not a treatment for any fibrotic disease and cannot replace an evaluation by the appropriate specialist.