Lan Wang

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by an abnormal epithelial‒mesenchymal transition (EMT) and fibroblast activation, although the molecular mechanisms driving these processes remain unclear. Here, we report that the expression of CCAAT enhancer binding protein γ (C/EBPγ), a transcription factor, is significantly upregulated in lung tissues from patients with IPF and the lungs of mice with bleomycin-induced fibrosis. In A549 epithelial cells, C/EBPγ overexpression promoted the EMT, as indicated by decreased E-cadherin expression and increased N-cadherin and vimentin expression. In MRC-5 fibroblasts, C/EBPγ overexpression increased cell migration and upregulated the expression of fibrotic markers, including collagen I, fibronectin, and α-SMA. Mechanistically, C/EBPγ activated the β-catenin pathway by stabilizing β-catenin through the transcriptional repression of AXIN1, a key component of the degradation complex. This repression occurred via an interaction with C/EBPα, antagonizing its promotion of AXIN1 expression, as confirmed by ChIP‒qPCR, luciferase assays, coimmunoprecipitation, immunofluorescence staining, and rescue experiments. In vivo, adeno-associated virus-mediated C/EBPγ overexpression aggravated bleomycin-induced pulmonary fibrosis in mice, increasing collagen deposition, inflammation, and β-catenin expression, whereas C/EBPγ knockdown alleviated these changes. Collectively, these findings suggest that the downregulation of C/EBPγ expression attenuates fibrosis progression through the C/EBPα–AXIN1–β-catenin axis, underscoring its involvement in β-catenin pathway regulation and advancing the understanding of IPF pathogenesis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by deregulated cell death programs that drive epithelial injury, fibroblast activation, and irreversible tissue remodeling. Multiple regulated cell death (RCD) modalities, including apoptosis, autophagy, necrosis, ferroptosis, pyroptosis, and cuproptosis, are implicated in IPF pathogenesis across epithelial cells, fibroblasts, macrophages, and endothelial cells. Apoptosis leads to alveolar epithelial cell loss and fibrosis initiation, whereas autophagy modulates fibroblast proliferation and extracellular matrix turnover. Necrosis amplifies inflammation; ferroptosis promotes epithelial dysfunction through lipid peroxidation; and pyroptosis activates the inflammasome pathway. Emerging evidence links cuproptosis, a copper‐dependent death mode, to fibrotic remodeling. These pathways are interconnected: apoptosis and autophagy can shift within the same cell, and epithelial apoptosis may induce macrophage pyroptosis, amplifying the profibrotic cascade. Emerging evidence indicates that these RCD modalities are coordinated through shared stress signals and regulatory nodes. Therapeutically, targeting RCD offers promising opportunities, with Bcl‐2 inhibitors for apoptosis, mTOR inhibitors for autophagy, iron chelators for ferroptosis, and early interventions for pyroptosis and cuproptosis. Targeting shared regulatory mechanisms or combining pathway‐directed strategies may further enhance efficacy. By balancing cell death and survival, these strategies could attenuate inflammation, restrict fibroblast‐driven scarring, and restore repair capacity. This review underscores the complexity and crosstalk of RCD in IPF, and proposes a conceptual framework for their coordinated regulation, highlighting its potential for therapeutic innovation.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disorder characterized by excessive scarring of lung tissue, predominantly affecting middle-aged and elderly populations. Oxidative stress plays a pivotal role in the pathogenesis of pulmonary fibrosis, disrupting redox homeostasis and driving fibrotic progression. Glutathione reductase (GSR), a key antioxidant enzyme, is essential for maintaining cellular glutathione (GSH) levels and mitigating oxidative damage. However, the specific involvement of GSR in IPF remains poorly understood. This study found that GSR levels were downregulated in IPF patients and mice treated with bleomycin (BLM). GSR knockdown enhanced epithelial-to-mesenchymal transition (EMT) in A549 cells and promoted the activation of MRC5 cells. Additionally, GSR depletion promoted cellular migration and senescence in both A549 and MRC5 cells. Mechanistically, silencing GSR in A549 and MRC5 cells led to a marked reduction in intracellular GSH levels, resulting in elevated reactive oxygen species (ROS) accumulation, thereby promoting the activation of the TGF-β/Smad2 signaling pathway. In conclusion, our findings demonstrate that GSR deficiency aggravates pulmonary fibrosis by impairing antioxidant defense mechanisms, promoting EMT, and activating fibroblasts through the TGF-β/Smad2 signaling. These findings suggest that GSR may be essential in reducing the fibrotic progression of IPF.

Long non-coding RNAs (lncRNAs) play critical roles in the process of lung tissue injury and repair which abnormal repair leads to disease including fibrosis, yet the physiopathology remains elusive. Here, we identified the lncRNA SYISL as a key regulator that is markedly upregulated in idiopathic pulmonary fibrosis (IPF) patients and bleomycin (BLM)-induced murine fibrotic lungs. Inhibition of SYISL significantly attenuates TGF-β1-driven fibroblast myofibroblast transition (FMT), a process confers to tissue injury repair and regeneration. Which demonstrates SYISL interaction with miR-23a function as a potent suppressor of fibrotic activation. Mechanistically, SYISL acts as a competing endogenous RNA (ceRNA) that directly binds miR-23a, thereby derepressing TRIO and F-actin binding protein (TRIOBP) via targeting its 3' untranslated region (UTR). Knockdown of TRIOBP amplifies the anti-fibrotic effects of miR-23a mimics while abolishing the pro-fibrotic activity of miR-23a inhibitors, establishing TRIOBP as a downstream effector of the SYISL/miR-23a axis. In vivo, intratracheal delivery of SYISL-targeting shRNA via adeno-associated virus (AAV) robustly reduces collagen deposition, hydroxyproline content, and expression of fibrotic markers in BLM-induced mice. Our findings elucidate a lncRNA-driven regulatory circuit in which SYISL promotes pulmonary fibrosis by sequestering miR-23a to elevate TRIOBP expression, nominating this axis as a novel therapeutic target for IPF.

Fibrosis is the process whereby cells at a damaged site are transformed into fibrotic tissue, comprising fibroblasts and an extracellular matrix rich in collagen and fibronectin, following damage to organs or tissues that exceeds their repair capacity. Depending on the affected organs or tissues, fibrosis can be classified into types such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis, and cardiac fibrosis. The primary pathological features of fibrotic diseases include recurrent damage to normal cells and the abnormal activation of fibroblasts, leading to excessive deposition of extracellular matrix and collagen in the intercellular spaces. However, the etiology of certain specific fibrotic diseases remains unclear. Recent research increasingly suggests that the cytoskeleton plays a significant role in fibrotic diseases, with structural changes in the cytoskeleton potentially influencing the progression of organ fibrosis. This review examines cytoskeletal remodeling and its impact on the transformation or activation of normal tissue cells during fibrosis, potentially offering important insights into the etiology and therapeutic strategies for fibrotic diseases.

Lung cancer is a major public health issue and heavy burden in China and worldwide due to its high incidence and mortality without effective treatment. It’s imperative to develop new treatments to overcome drug resistance. Natural products from food source, given their wide-ranging and long-term benefits, have been increasingly used in tumor prevention and treatment. This study revealed that Hibiscus manihot L. flower extract (HML) suppressed the proliferation and migration of A549 cells in a dose and time dependent manner and disrupting cell cycle progression. HML markedly enhanced the accumulation of ROS, stimulated the dissipation of mitochondrial membrane potential (MMP) and that facilitated mitophagy through the loss of mitochondrial function. In addition, HML induced apoptosis by activation of the PTEN-P53 pathway and inhibition of ATG5/7-dependent autophagy induced by PINK1-mediated mitophagy in A549 cells. Moreover, HML exert anticancer effects together with 5-FU through synergistic effect. Taken together, HML may serve as a potential tumor prevention and adjuvant treatment for its functional attributes.

Pulmonary fibrosis (PF) is an interstitial lung disease characterized by the destruction of the pulmonary parenchyma caused by excessive extracellular matrix deposition. Despite the well-known etiological factors such as senescence, aberrant epithelial cell and fibroblast activation, and chronic inflammation, PF has recently been recognized as a metabolic disease and abnormal lipid signature was observed both in serum and bronchoalveolar lavage fluid (BALF) of PF patients and mice PF model. Clinically, observational studies suggest a significant link between high-fat diet (HFD) and PF as manifested by high intake of saturated fatty acids (SFAs) and meat increases the risk of PF and mice lung fibrosis. However, the possible mechanisms between HFD and PF remain unclear. In the current review we emphasize the diversity effects of the epigenetic dysregulation induced by HFD on the fibrotic factors such as epithelial cell injury, abnormal fibroblast activation and chronic inflammation. Finally, we discuss the potential ways for patients to improve their conditions and emphasize the prospect of targeted therapy based on epigenetic regulation for scientific researchers or drug developers.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by fibroblast activation, excessive deposition of extracellular matrix, and progressive scarring; the pathogenesis remains elusive. The present study explored the role of Tribbles pseudokinase 3 (TRIB3), a well-known stress and metabolic sensor, in IPF. TRIB3 is down-regulated in the lungs of IPF patients in comparison to control subjects. Deficiency of TRIB3 markedly inhibited A549 epithelial cells’ proliferation and migration, significantly reducing wound healing. Conversely, overexpression of TRIB3 promoted A549 cell proliferation and transmigration while it inhibited its apoptosis. Meanwhile, overexpressed TRIB3 inhibited fibroblast activation and decreased ECM synthesis and deposition in MRC5 cells. TRIB3 attenuated pulmonary fibrosis by negative regulation of ATF4, while TRIB3 expression markedly inhibited ATF4 promoter-driven transcription activity and down-regulated ATF4 expression. A co-culture system showed that TRIB3 is important to maintain the normal epithelial–mesenchymal crosstalk and regulate fibroblast activation. Taken together, our data suggested that an axis of TRIB3–ATF4 is a key mediator in IPF which might be a potential target for fibroproliferative lung disease treatment.