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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease in which the alveoli become filled with excessive extracellular matrix—the “scaffolding material” of the lung. As a result, the once soft and elastic lungs turn stiff and brittle, like a sponge sealed in cement, losing their ability to expand and contract normally[1].Even more alarming, the median survival time for IPF patients is only 2-4 years—shorter than that of many cancers.
In the past, it was believed that this “scaffolding material” mainly came from excessive secretion by fibroblasts. However, recent studies have revealed that alveolar type II epithelial cells (ATII)—the “caretakers” of the lungs-play a pivotal role. When these cells malfunction, they actively “orchestrate” lung fibrosis, further exacerbating the disease[2].
Figure 1. Key processes inducing pulmonary fibrosis. Repetitive injuries in human adult lung lead to damaged ATII cells (orange)[2].
Unmasking the Mastermind: The “Runaway Switch” YAP Protein
Using single-cell RNA sequencing (scRNA-seq), scientists discovered that in the ATII cells of IPF patients, YAP protein is abnormally active-like a “switch gone out of control”[3].
Under normal conditions, YAP regulates cell growth and repair, but in IPF, it becomes “overactivated” (Fig. 2A). Immunohistochemical analysis of control and IPF tissues confirmed the scRNA-seq findings, showing increased nuclear YAP activity predominantly in alveolar epithelial cells associated with visible epithelial remodeling, while TAZ expression was mainly observed in mesenchymal cells within fibrotic regions (Fig. 2B).
Importantly, abnormal YAP activation was also detected in IPF lung areas exhibiting only moderate histological damage, suggesting that YAP alteration may be an early event in IPF development (Fig. 2B). In fibrotic mouse lungs, even in “apparently normal” regions-including ATII cells labeled with DC-Lamp-nuclear YAP/TAZ levels were subjectively elevated (Fig. 2C). Notably, these areas had not yet undergone extensive remodeling, and lung stiffness remained within the normal range.
These findings strongly support the hypothesis that YAP becomes active and begins to “stir up trouble” even before the lung shows obvious stiffening-indicating that YAP could serve as a promising target for early intervention in IPF.
Figure 2. YAP/TAZ is upregulated and active in the aberrant epithelium in IPF[3].
A. Publicly available scRNA-Seq data showing cell type specific gene expression in distal (alveolar) epithelial cells of IPF and Donor (Ctrl) lungs (IPFcellatlas.com: GSE135893).
B. Representative Immunohistochemical staining of YAP, TAZ, epithelial, and mesenchymal markers on tissue sections for Donor tissue, moderate-fibrotic IPF, and full fibrotic IPF tissues. n = 6 donor, n = 6 moderate-fibrotic IPF, n = 13 full fibrotic IPF.
C. Representative immunofluorescence staining of Yap/Taz and Dc-Lamp, a marker of alveolar type II cells, on paraffin sections of murine lungs from PBS and bleomycin treated mice after 14 days. Scalebar 20 um on the top row. Bottom row is a digital zoom 5x. n = 5 PBS, n = 8 Bleomycin.
D. Principal component analysis (PCA) of microarray analysis on samples from control subjects (n = 91), IPF (n = 100), and COPD (n = 144) patients from the Lung Genome Research Consortium (LGRC) dataset using Hippo pathway genes found in Supplementary Table 1.
YAP’s Accomplice: LOX - The “Super Glue” That Hardens the Lungs
YAP doesn’t act alone - its key accomplice is lysyl oxidase (LOX). After isolating primary normal and fibrotic ATII cells from mouse lungs, researchers found that nuclear expression of YAP/TAZ was significantly increased in fibrotic ATII cells, whereas YAP/TAZ mainly localized in the cytosol of normal ATII cells (Fig. 3A, B). The study confirmed LOX gene and protein expression in ATII cells, which decreased after YAP/TAZ gene silencing. This suggests that YAP/TAZ-mediated regulation of LOX expression in fibrotic ATII cells may contribute to the formation of a fibrotic extracellular matrix microenvironment (Fig. 3D, E).
LOX functions like a “super glue,” responsible for crosslinking collagen fibers. Under normal conditions, it works moderately to maintain the structural integrity of the lung scaffold; however, under excessive YAP activation, LOX is overproduced, causing excessive collagen crosslinking and the formation of stiff fibrotic scars.
Data show that in IPF patients, LOX expression in ATII cells and aberrant basal-like cells is markedly higher than in healthy individuals and is strongly correlated with YAP activity. In human lung tissue sections, LOX protein accumulates precisely in alveolar regions where YAP is active, forming a vicious “YAP-LOX-collagen” cycle - the stiffer the lung becomes, the more active YAP is; and the more active YAP becomes, the stiffer the lung grows (Fig. 3H).
Figure 3. YAP/TAZ in fibrotic ATII cells regulate LOX secretion and collagen crosslinking[3].
A. Representative immunofluorescence images (20× objective) of YAP/TAZ and E-cadherin in primary murine (pm) ATII cells isolated from fibrotic and control murine lungs and plated on glass cover slips (200,000/cm2 ) (n = 5 each group). Scale bar = 50 μm.
B. Quantification of YAP/TAZ positive cells in healthy and fibrotic ATII cells in (A). Quantification by image J of 5 independent pmATII isolates each, 5 fields per sample. Y-Axis depicts percent of ECAD positive ATII cells with nuclear YAP/TAZ staining, Mean ± s.d. ***p < 0.0001 unpaired, two-tailed t-test. p = 0.0003.
C. Schematic of experiments to silence Yap/Taz using siRNA (siYT) and the corresponding analyses.
D. Heatmap of matrix genes from microarray data of pmATII cells isolated from bleomycin treated mice vs PBS treated mice followed by siRNA-mediated silencing of Yap/Taz (siYT), n = 3. Left 3 columns show fold change expression in fibrotic ATII cells normalized with fold change expression in healthy ATII cells. Right 3 columns show fold change expression in fibrotic ATII cells subjected to siYT normalized with scramble control (sc).
E. Gene expression of lysl oxidase (Lox) in pmATII cells isolated from normal and fibrotic mice and culture with siYT, n = 3 independent isolations. Mean ± s.d. *p < 0.05 paired one-way ANOVA with repeated measures and pre-selected comparisons. Corrected for multiple comparisons using Šídák’s multiple comparisons test. PBS-sc vs. PBS-siYT (p = 0.1002); PBS-sc vs Bleo-sc (p = 0.0106); Bleo-sc vs. Bleo-siYT (0.0373).
F. Immunoblotting of Lox in the supernatants of study described in (C).
G. LOXfamily members are elevated in epithelial cells in IPF tissue sections, with LOX prominently elevated in comparison to other LOX-family members.
H. YAP, LOX staining with HTII-280 (a marker of ATII cells) in human lung sections of control and IPF tissue showing localization of LOX in areas of aberrant alveolar remodeling. Source data for Panels (B, E and F) are provided as a Source Data file. Source Data for Panel (D) is deposited E-MTAB-14643 and (H) is deposited at S-BIAD1520
A Ready-to-Use “Defuser”: Surprising Power of an Old Drug
If YAP is the culprit, could inhibiting it help? Scientists turned to Verteporfin (Vp) - an FDA-approved drug originally developed for eye diseases. The results were astonishing.
• In mice:
When Verteporfin was used to inhibit YAP in a Bleomycin-induced pulmonary fibrosis model, survival rates jumped from 62.5% to 93.7% (PBS-veh: 10/10; PBS-VP: 10/10; Bleo-veh: 10/16; Bleo-VP: 15/16) (Fig. 4A). Treated mice showed reduced cellular infiltration and tissue density (Fig. 4B, C), decreased collagen content (Fig. 4D), and significantly improved lung function.
Figure 4. Pharmacological inhibition of YAP-TEAD improves survival and attenuates experimental lung fibrosis in vivo[3].
A. Survival analysis during 14 days of mice treated with PBS and Bleomycin (2U/kg) with or without verteporfin (VP) injections administered intraperitoneally every 48 h starting from day 7 to day 14 (45 mg/kg).
B. Representative Masson’s trichrome staining of paraffin sections of PBS and Bleomycin mouse lungs treated with VP, scale bar: 2 mm. All animals were stained thus n = 10 for both PBS groups and n = 10 for Bleomycin and n = 15 for Bleomycin-VP.
C. Modified Ashcroft Score of the histological staining of the mouse lungs described in (A), each dot represents the median score of 3 independent experts who performed blinded analysis on digitized histological slides containing multiple sections per animal.
D. Collagen amount as measured by high performance liquid chromatography of total tissue homogenates of mouse lungs described in (A); Each dot represents an individual mouse who survived until day 14 of the study.
• In human lung tissue:
When Verteporfin was applied to precision-cut lung slices from IPF patients, it significantly reduced LOX activity (Fig. 5B-D). Because LOX drives collagen crosslinking, its inhibition led to a decrease in collagen stiffness - effectively softening the scar tissue that had hardened the lungs.
Figure 5. YAP-TEAD inhibition by verteporfin reduces LOX and fibrotic markers in human fibrotic lung tissue ex vivo[3].
A. Schematics for precision-cut lung slice (PCLS) generation from donor lung and treatment with the fibrosis cocktail (FC) and verteporfin (VP) ex vivo for 5 days.
B. LOX gene expression of in PCLS treated with the fibrosis cocktail and VP, n = 5 patients for CC and n = 6 for FC conditions; Two-way ANOVA with uncorrected Fisher’s LSD.
C, D. Immunoblotting and quantification of LOX in supernatants obtained from PCLS in study described in Fig. 7A; (*p < 0.05, paired t-test and ns unpaired t-test). Stain-Free technology is shown for qualitative evaluation only as an estimation of total protein in supernatants; it is not used for quantification in (D) as it labels tryptophan amino acids which are not present in collagen and thus underestimates total protein amounts in supernatants (see Supplementary Fig. S17 legend for further details). Quantification in (D) was performed on the LOX detected in the separate blots, run in parallel, shown in Panel (C) and Supplementary Fig. S17. PCLS derived from individual patients were run on the same blots to permit relative comparisons for the patient’s own control conditions. *p < 0.05 as assessed by Twoway ANOVA with uncorrected Fisher’s LSD.
The mechanism by which Verteporfin acts is like a precise “molecular switch.” YAP must bind to its partner TEAD to form a complex that initiates a cascade of downstream gene expression programs promoting fibrosis. Verteporfin functions as an “obstacle” that specifically blocks the interaction between YAP and TEAD. Once Verteporfin enters the cell, it binds to the YAP protein and alters its conformation, preventing normal interaction with TEAD and thereby disrupting the formation of the YAP-TEAD complex. This fundamentally cuts off the transmission of fibrotic signals, suppressing subsequent events such as LOX upregulation and excessive collagen crosslinking that drive lung fibrosis. It effectively stops the initial “domino” that triggers pulmonary fibrosis, halting the progressive worsening of the disease.
Figure 6. The Hippo-YAP/LOX mediated extracellular matrix (ECM) remodeling cycle driven by lung epithelial cells in IPF[3].
What This Means for IPF Patients
• Early intervention could reverse disease progression:
Since YAP activation occurs early, detecting it may enable early diagnosis and treatment.
• Drug repurposing accelerates therapy development:
Because Verteporfin is already approved, it could reach clinical application much faster.
• Potential beyond IPF:
The YAP-TEAD pathway is also implicated in liver and cardiac fibrosis, meaning this discovery could benefit patients with other fibrotic diseases as well.
Although more clinical trials are needed, this study opens a promising new window of hope for those suffering from IPF.
Summary
If you or someone you know experiences chronic coughing or shortness of breath, don’t ignore it - seek medical attention early. Meanwhile, scientists are unraveling the molecular “code” behind lung hardening, bringing us closer to a future where this devastating disease can be effectively managed - or even reversed.
a photosensitizer used in photodynamic therapy for treating ocular conditions such as age-related macular degeneration. Functions as a YAP inhibitor, disrupting YAP-TEAD interactions. Also induces apoptosis and inhibits autophagy by blocking autophagosome formation.
a TEAD PROTAC degrader that selectively degrades TEAD1 (DC50 = 3 nM) with strong affinity for TEAD2, TEAD3, and TEAD4 (Ki = 2.0, 3.6, and 1.6 nM, respectively).
