Pulmonary fibrosis (PF) is a chronic, progressive interstitial lung disease characterized by excessive deposition of extracellular matrix (ECM) and abnormal fibroblast proliferation, which is mainly caused by air pollution, smoking, aging, occupational exposure, environmental pollutants exposure, and microbial infections. Although antifibrotic agents such as pirfenidone and nintedanib, approved by the United States (US) Food and Drug Administration (FDA), can slow the decline in lung function and disease progression, their side effects and delivery inefficiency limit the overall prognosis of PF. Therefore, there is an urgent need to develop effective therapeutic targets and delivery approaches for PF in clinical settings. This review provides an overview of the pathogenic mechanisms, therapeutic drug targeting signaling pathways, and promising drug delivery strategies for treating PF.

Pulmonary fibrosis is a chronic and progressive interstitial lung disease associated with the decay of pulmonary function, which leads to a fatal outcome. As an essential epigenetic regulator of DNA methylation, the involvement of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) in fibroblast activation remains largely undefined in pulmonary fibrosis. In the present study, we found that TGF-β1–mediated upregulation of UHRF1 repressed beclin 1 via methylated induction of its promoter, which finally resulted in fibroblast activation and lung fibrosis both in vitro and in vivo. Moreover, knockdown of UHRF1 significantly arrested fibroblast proliferation and reactivated beclin 1 in lung fibroblasts. Thus, intravenous administration of UHRF1 siRNA–loaded liposomes significantly protected mice against experimental pulmonary fibrosis. Accordingly, our data suggest that UHRF1 might be a novel potential therapeutic target in the pathogenesis of pulmonary fibrosis.

Silicosis is a chronic fibrotic pulmonary disease caused by consistent inhalation of respirable crystalline-free silica dust. The senescence of alveolar epithelial type II cells (ATII) is considered the initiation of pulmonary fibrosis. As a secreted protein, growth differentiation factor 15 (GDF15) was found intimately associated with the severity of lung diseases via senescence. Therefore, we speculate that GDF15 may involved in silica-induced pulmonary fibrosis. Co-culture was performed to observe the pro-fibrotic effect of GDF15, which is secreted from the silica-induced senescence ATII cells, on peripheral effector cells. We further explored GDF15-related signaling pathways via ChIP and IP assays. GDF15 siRNA lipid nanoparticles, anti-aging compound β-nicotinamide mononucleotide (NMN), and the Chinese traditional drug Bazibushen (BZBS) were used individually to intervene silicosis progress. SiO₂ and etoposide-stimulated MLE-12 cells showed senescence phenotype and secreted substantial GDF15, which is consistent with over-expressed GDF15 in lung tissues from silica-induced pulmonary fibrosis. The results further demonstrated that senescence ATII cells could facilitate co-cultured epithelial cell epithelial-mesenchymal transition (EMT) and fibroblast activation in a GDF15-dependent manner. Mechanistically, p53 regulates GDF15 transcription and secretion in senescence ATII cells. Moreover, secreted GFD15 performed its pro-fibrotic role by directly binding to TGF-βR via autocrine and paracrine manners. Also, lipid nanoparticles targeting GDF15 or cell senescence inhibitor NMN and BZBS showed efficient anti-fibrotic effects in vivo. Our results elucidate that senescence ATII cell-secreted GDF15 plays a vital role in promoting silicosis by influencing surrounding cells, and provides scientific clues for the selection of potential therapeutic drugs for silicosis.

Nanoplastics (NPs) have emerged as pervasive environmental pollutants, and polystyrene nanoplastics (PS-NPs) have been increasingly implicated in pulmonary toxicity and fibrosis. Here, we established both an in vitro BEAS-2B bronchial epithelial injury model and an in vivo mouse model by repeated oropharyngeal aspiration of PS-NPs. We observed pronounced pulmonary fibrosis and ferroptotic death of alveolar type II cells. Integrated transcriptomic and proteomic profiling highlighted enrichment of the ferroptosis pathway, and in vitro and in vivo experiments confirmed that PS-NPs suppress GPX4 while inducing FTL, thereby driving lipid peroxidation. Mechanistically, YY1 binds the FTL promoter to repress its expression, and YY1 knockdown alleviates ferroptosis and fibrosis. Our findings identify YY1/FTL-mediated ferroptosis as a key mechanism by which PS-NPs induce pulmonary fibrosis.

Silicosis, an age-related disease, is still a heavy burden on global occupational health. Emerging evidence has revealed that targeting senescent cells may be a promising therapeutic strategy for silicosis. This study was designed to investigate the novel function of Bazibushen (BZBS), a known anti-aging drug, in improving silica-induced lung fibrosis. We first confirmed the accumulation of senescent fibroblasts in the fibrotic regions of silicotic lungs. In both young (6-8 weeks) and aged (12 months) silicotic mice, BZBS exhibited anti-fibrosis and anti-senescence effects. Results of in vitro experiments showed the ability of BZBS to block the expression of p21, fibrotic markers, and senescence-associated secretory phenotype factors. Furthermore, BZBS was observed to attenuate mitochondrial dysfunction in senescent fibroblasts through FOXO1/PINK1/Parkin signaling. Collectively, these results indicated BZBS as a potential anti-fibrosis agent, which exerted its role through maintaining mitochondrial homeostasis in senescent fibroblasts.