As the core mechanism of TGF-β1 signal transduction, the Smad pathway comprises three functionally distinct protein families: receptor-activated Smads (R-Smads, including Smad2/3), common-mediator Smads (co-Smads, Smad4), and inhibitory Smads (I-Smads, Smad6/7). Following ligand-receptor binding, TβRII phosphorylates and activates TβRI, which subsequently activates R-Smads through phosphorylation of their C-terminal SSXS motif. The phosphorylated R-Smads form a heterotrimeric complex with co-Smad, which translocates into the nucleus. There, it interacts with chromatin remodeling and transcriptional regulatory elements to activate or repress target gene expression (Gao et al., 2024) (Figure 1). Notably, Davis et al. discovered that R-Smads can form functional complexes with microRNAs, participating in the post-transcriptional regulation of gene expression by inducing RNA degradation, revealing a multi-layered regulatory mechanism within the Smad signaling network (Davis-Dusenbery and Hata, 2011).

I-Smads inhibit the phosphorylation of R-Smads by competitively binding to TβRI, while concurrently cooperating with Smad ubiquitination regulatory factors to promote the ubiquitination and degradation of the receptor complex, thereby achieving dynamic negative regulation of TGF-β1 signaling. This bidirectional regulatory mechanism ensures the precision and reversibility of signal transduction.

In addition to the canonical Smad pathway, TGF-β1 can activate various alternative signaling cascades, including the mitogen-activated protein kinase (MAPK) cascade, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, and cytoskeletal remodeling mediated by Rho family small GTPases (e.g., Rac/Cdc42) (Hamidi et al., 2017).

The chronic immune-inflammatory response triggered by biomass smoke exposure is a significant driver of airway remodeling. Alveolar macrophages (AMs), as key regulators of pulmonary immune homeostasis, undergo phenotypic polarization (switching from pro-inflammatory M1 to anti-inflammatory M2), which is closely associated with the dynamic expression of TGF-β1 (Gordon, 2003). Experiments by Wang et al. (2022) showed that AMs release pro-inflammatory factors causing tissue damage during the initial phase of biomass smoke exposure, whereas sustained exposure for 6 months was accompanied by a significant increase in TGF-β1 and enhanced M2 polarization. M2 macrophages highly express arginase-1 (Arg-1) and chitinase-3-like protein 3 (Ym-1). They not only suppress inflammatory responses but also directly participate in fibroblast activation and ECM deposition by secreting pro-fibrotic factors such as TGF-β1 and PDGF (Mills et al., 2000), indicating that TGF-β1 contributes to the remodeling process by regulating macrophage phenotypic switching.

Furthermore, the role of the Th17/IL-17A axis in airway remodeling has garnered significant attention. Biomass smoke can promote dendritic cell maturation via the TGF-β1/STAT3 pathway, thereby inducing the differentiation of naïve CD4⁺ T cells into Th17 cells, which secrete IL-17A (Solleiro-Villavicencio et al., 2015; Pu et al., 2021). IL-17A, acting as a core mediator of both pro-inflammatory and pro-fibrotic effects, can directly activate fibroblasts, upregulate the expression of collagen genes such as COL1A1 and COL3A1, and enhance metalloproteinase-9 (MMP-9) activity to promote ECM remodeling. Notably, IL-17A can also amplify TGF-β1 signaling through a positive feedback loop: on one hand, IL-17A induces the expression of TGF-β1 precursor by activating the NF-κB pathway; on the other hand, it reinforces TGF-β1/Smad signal transduction by suppressing Smad7 expression, thereby establishing a pro-fibrotic cascade (Huo et al., 2021).

Recent studies have also elucidated the synergistic roles of innate lymphoid cells (ILCs) and regulatory T cells (Tregs) in immune dysregulation. ILC2s increase following biomass smoke exposure and collaborate with TGF-β1 by secreting IL-13 to promote fibroblast transformation (Rosário Filho et al., 2021). Although Tregs possess anti-inflammatory functions, in a TGF-β1-dominated microenvironment, they may indirectly contribute to the fibrotic process by expressing glycoprotein A repetitions predominant (GARP), which facilitates the activation of latent TGF-β1 (Moreau et al., 2022). The dysregulation of this immune cell network collectively establishes a chronic inflammatory microenvironment centered around TGF-β1 with multicellular interactions, ultimately leading to irreversible airway structural remodeling.

Aberrant fibroblast activation and excessive ECM deposition are core pathological features of airway remodeling. Studies indicate that TGF-β1 plays a key role in airway structural reconstruction by inducing fibroblast proliferation, myofibroblast transdifferentiation, and the overproduction of matrix components such as collagen (Paw et al., 2023; Guan et al., 2020). Consequently, TGF-β1-induced fibroblast activation models have become important in vitro tools for studying airway remodeling. Under physiological conditions, lung fibroblasts maintain low proliferative activity, but can transition to a high-secretory phenotype upon stimulation by an inflammatory microenvironment. Experimental evidence shows that human lung fibroblasts exposed to biomass smoke extract exhibit upregulated expression of TGF-β1 and type I/III collagen within just 3 h, suggesting that environmental exposure can drive fibroblast activation via the TGF-β1 pathway (Recillas-Román et al., 2021). Notably, the dynamic imbalance between ECM synthesis and degradation is a crucial mechanism leading to excessive matrix accumulation. TGF-β1 contributes to this process through dual regulation: it promotes the biosynthesis of ECM components like collagen, while simultaneously inhibiting the degradative activity of matrix metalloproteinases (MMPs), thereby disrupting ECM metabolic equilibrium (Savin et al., 2023; Hough et al., 2020; Murray and Wynn, 2011).

The canonical Smad signaling pathway is the primary molecular mechanism through which TGF-β1 mediates airway remodeling. Research by Song et al. found that TGF-β1 can facilitate the phosphorylation and nuclear translocation of STAT3/6 by forming a Smad3/JAKs/STAT3/6/EPRS multi-protein complex, thereby activating the transcriptional program of ECM-related genes (Song et al., 2018). Furthermore, microRNA-21 was shown in an asthma model to regulate collagen and pro-fibrotic gene expression via the TGF-β1/Smad7 signaling axis, and its inhibitor significantly alleviated the degree of airway remodeling (Hur et al., 2021). Recent studies have revealed the involvement of various non-canonical pathways in TGF-β1-mediated fibrosis, including the MAPK cascade, the PI3K/Akt pathway, and the Rac/Cdc42 pathway, among others (Hamidi et al., 2017).

EMT is a core pathological process in airway remodeling, characterized by the loss of epithelial cell polarity and the acquisition of a mesenchymal phenotype. Research demonstrates that TGF-β1 has a potent EMT-inducing effect on alveolar and bronchial epithelial cells, a process that can be recapitulated in in vitro culture models and animal experiments (Willis et al., 2005; Zhang et al., 2009). He et al. (2017) established a rat model exposed to biomass smoke for 7 months and found a significant positive correlation between serum TGF-β1 levels and the expression of bronchial epithelial mesenchymal markers (FSP1, vimentin), providing direct evidence that biomass smoke promotes EMT via the TGF-β1 pathway, leading to airway remodeling. Current research has elucidated multiple molecular mechanisms through which TGF-β1 induces EMT.

c-Jun N-terminal kinase 1 (JNK1) is a critical regulatory node in TGF-β1-mediated EMT. Experiments confirmed that JNK1 cooperatively activates EMT-related transcriptional programs by forming a phosphorylation complex with Smad3. In JNK1 knockout mice, the pulmonary fibrosis and airway remodeling phenotypes induced by bleomycin or house dust mite were completely abolished, indicating the necessity of this kinase in the EMT process (van der Velden et al., 2020). TGF-β1 forms a positive feedback loop with matrix MMP-9. TGF-β1 induces MMP-9 expression, which promotes basement membrane degradation, while MMP-9 can further activate the signaling pathway by releasing latent TGF-β1. In the airways of COPD patients, this loop leads to abnormal deposition of EMT-derived mesenchymal cells, exacerbating airway wall fibrosis (Cabrera-Benítez et al., 2012). Mitogen-activated protein kinase 19 (MAPK19), a newer member of the MAPK family, was found to synergize with Mycobacterium bovis BCG to activate the TGF-β/Smad2 pathway, inducing EMT in type II alveolar epithelial cells. Blocking this pathway with the specific inhibitor LY2109761 significantly reduced the proportion of EMT cells and collagen deposition (Xia et al., 2024).

Although the aforementioned mechanisms have been validated in various pulmonary diseases, the specific regulatory network of TGF-β1-mediated EMT in CMBS remains to be fully elucidated. Future research should integrate single-cell sequencing and spatial transcriptomic technologies to decipher the spatiotemporal dynamics of airway epithelial EMT and identify its pivotal molecular drivers under biomass smoke exposure.

Bronchoscopy in CMBS patients often reveals features such as tortuous and hyperplastic mucosal vasculature, increased wall fragility, and a tendency for bleeding, indicating that vascular remodeling is a significant pathological alteration (Lu et al., 2022). Animal experiments show that biomass smoke exposure for 6 months concurrently upregulates the expression of both TGF-β1 and vascular endothelial growth factor (VEGF) in rat lung tissue (Wang et al., 2022), suggesting that TGF-β1 may play a central regulatory role in CMBS-associated vascular remodeling. At the molecular level, TGF-β1 induces the transition of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic phenotype via Smad pathways (e.g., activation of the Smad2/3-Smad4 complex) and non-Smad pathways (e.g., JNK and ERK). This is characterized by downregulation of α-smooth muscle actin (α-SMA) and upregulation of pro-proliferative proteins such as osteopontin (OPN), vimentin, and proliferating cell nuclear antigen (PCNA) (Wang et al., 2022; Da et al., 2023).

Significant crosstalk exists between the TGF-β1 and VEGF signaling pathways: on one hand, TGF-β1 upregulates VEGF-A expression through Smad3-mediated transcriptional activation; on the other hand, it enhances the expression and phosphorylation of VEGFR2, thereby amplifying pro-angiogenic signals (Yan et al., 2020). Notably, TGF-β1 differentially regulates members of the VEGF family; for instance, it inhibits VEGF-D expression in human lung fibroblasts via the JNK pathway, potentially affecting the balance between angiogenesis and lymphangiogenesis (Cui et al., 2014).

Although research directly linking biomass smoke to pulmonary vascular remodeling is limited, cigarette smoke models provide strong corroborative evidence. Cigarette smoke extract can induce abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) via the ERK pathway and promote VSMC migration through upregulation of OPN in animal models (Su et al., 2021; Zhou et al., 2024). Both biomass smoke and cigarette smoke are rich in PM2.5 and may cause vascular pathology through shared mechanisms such as oxidative stress and chronic inflammation. Recent studies suggest that biomass combustion smoke may induce hypermethylation of the EDN1 gene, regulating endothelin-1 (ET-1) levels and participating in vascular remodeling (García-Carmona et al., 2025). Macrophages also play a key role in regulating the vascular microenvironment, either by secreting TGF-β1 or through pathways such as FOXO1-SEMA3C (Niimi et al., 2024).

In summary, TGF-β1 can drive vascular remodeling in CMBS by regulating VSMC phenotypic switching and VEGF signaling through a multi-pathway network. Biomass smoke may share some pathogenic mechanisms with cigarette smoke, but its specific components and epigenetic regulatory pathways require further investigation.

Fresolimumab is a broad-spectrum, fully human monoclonal antibody that neutralizes TGF-β1, β2, and β3. In fibrotic disease research, this drug significantly reduced the expression of TGF-β-regulated genes (SERPINE1, CTGF) and decreased dermal myofibroblast infiltration in patients with systemic sclerosis (Rice et al., 2015). It also demonstrated good safety and potential for slowing renal function decline in patients with primary focal segmental glomerulosclerosis (Trachtman et al., 2011; Vincenti et al., 2017). Its safety profile, characterized by reversible skin toxicity, supports the possibility of long-term administration. Given that CMBS is also characterized by TGF-β1-driven fibrosis, fresolimumab holds promise for blocking biomass smoke-induced airway fibrosis by neutralizing multiple TGF-β isoforms. Its safety profile with reversible skin toxicity also supports the potential for long-term use.

Galunisertib (LY2157299) is an oral TβRI kinase inhibitor that blocks TGF-β signal transduction by competitively binding to the ATP-binding site of TβRI, thereby inhibiting Smad2/3 phosphorylation. Galunisertib shows great promise in treating fibrotic diseases. Studies have confirmed its significant inhibitory effects on pathological processes such as dermal fibroblast fibrosis, liver fibrosis, and renal fibrosis (Peterson et al., 2022; Hammad et al., 2018; van Leeuwen et al., 2024). Its favorable safety profile, particularly the absence of significant cardiovascular toxicity, offers an advantage for long-term use in chronic respiratory diseases. Based on these findings, galunisertib holds potential for directly targeting the airways via local inhalation administration to inhibit the fibrotic process in the bronchial walls of CMBS patients.

TEW-7197 (vactosertib) is another highly selective TβRI inhibitor. Preclinical studies have confirmed its efficacy in inhibiting fibrosis progression in models of liver, kidney, and pulmonary fibrosis (Park et al., 2015). Recent research has explored its potential for respiratory application. Surface-engineered mesenchymal stem cells constructed via bioconjugation technology (combining TEW-7197 and linifanib) effectively suppressed subepithelial fibrosis and angiogenesis in an asthma model (He et al., 2024). This delivery strategy offers a novel approach for CMBS treatment, whereby TEW-7197 could be delivered directly to the airway lesions via a targeted drug delivery system, maximizing therapeutic efficacy while minimizing systemic exposure.

LY3200882 is a dual TβRI/ALK5 inhibitor. Preclinical studies have confirmed its ability to enhance the anti-tumor immune response to radiotherapy (Hamon et al., 2022). Although there are no published reports on this compound in fibrotic diseases to date, its mechanism of action still provides important rationale for targeting the TGF-β signaling pathway. Notably, a tumor microenvironment-responsive drug delivery system developed by Li et al. (2022) offers an innovative concept for local treatment strategies in CMBS. Drawing on such advanced technologies, future efforts could design intelligent responsive drug delivery systems tailored to the characteristics of the airway inflammatory microenvironment in CMBS (e.g., specific protease activity or pH changes). This would enable the precise and controlled release of TGF-β inhibitors at the site of bronchial stenosis, thereby improving the efficiency and safety of targeted therapy.

Although TGF-β-targeting drugs show promising therapeutic potential in fibrotic diseases, their application in CMBS faces several challenges. Firstly, current research on TGF-β pathway inhibition primarily focuses on diseases like cancer and fibrosis; their efficacy, optimal dosing, and long-term safety in CMBS remain unclear and urgently require evaluation through rigorous preclinical and clinical studies. Secondly, the route of administration needs optimization. Developing inhaled formulations could achieve local drug enrichment in the airways, enhance targeting, and reduce systemic exposure risk, thereby improving the risk-benefit ratio of treatment. Furthermore, it is necessary to establish patient stratification strategies based on imaging characteristics (e.g., degree and distribution of bronchial stenosis) and molecular biomarkers (e.g., levels of TGF-β1, p-Smad3) to accurately identify CMBS subpopulations most likely to benefit from anti-TGF-β therapy. Concurrently, combination regimens of TGF-β inhibitors with existing anti-fibrotic drugs (e.g., pirfenidone) should be actively explored to achieve synergistic inhibition of the fibrotic process. Future research should prioritize the establishment of CMBS animal models that simulate biomass smoke exposure. Systematically validating the efficacy and safety of TGF-β-targeting drugs in such models will provide a solid theoretical foundation for subsequent clinical trials.