Idiopathic Pulmonary Fibrosis (IPF) is a devastating interstitial lung disease characterized by the progressive replacement of functional lung tissue with fibrotic scar tissue, leading to impaired gas exchange and ultimately respiratory failure (Raghu et al., 2022). The etiology of IPF remains obscure, and despite recent advances in understanding its pathogenesis, the disease continues to carry a poor prognosis, with a median survival time of only three to 5 years following diagnosis (Liu et al., 2022a). The complexity of IPF’s pathogenesis, which encompasses chronic inflammation, dysregulated wound healing, and microenvironmental changes that drive fibroblast proliferation and extracellular matrix deposition, poses significant challenges for disease management (Mei et al., 2021).

Current pharmacotherapeutic options for IPF are limited, primarily focusing on slowing disease progression and alleviating symptoms. Anti-fibrotic agents, such as pirfenidone and nintedanib, have demonstrated modest benefits in slowing the decline in lung function (Flaherty et al., 2019; Finnerty et al., 2021). However, these treatments are associated with significant side effects and high costs, highlighting the need for alternative or complementary therapeutic strategies.

Ginkgo biloba L. extract (GBE) is a mixture with various pharmacological effects extracted and processed from Ginkgo biloba leaves, and its main active ingredients are 22%–27% flavonoids (quercetin, etc.), 5%–7% terpene lactones (ginkgolides, bilobalide, etc.), organic acids and phenols (Kulić et al., 2022). The oral formulation contains 19.2 mg of total flavonoid glycoside and 4.8 mg of terpenoid lactone or 9.6 mg of total flavonoid glycoside and 2.4 mg of terpenoid lactone. Recently, it has gained scientific attention for its potential anti-inflammatory, antioxidant, and vasorelaxant properties (Hu et al., 2024; Liu et al., 2024a). Clinical trials have explored GBE’s efficacy in enhancing memory, attention, and other cognitive domains, with some studies indicating a positive impact in both healthy individuals and those with mild cognitive impairment (Xiao et al., 2024). Beyond cognitive enhancement, GBE’s antioxidant and vasodilatory properties have prompted investigations into its potential role in treating cardiovascular diseases (Liu et al., 2024b). Furthermore, its anti-inflammatory and antioxidant effects have led to studies examining the use of GBE in respiratory conditions, such as IPF. Preclinical studies suggest that GBE may modulate key pathways involved in IPF pathogenesis, including the inhibition of pro-inflammatory cytokines, reduction of oxidative stress, and improvement of endothelial function (Zhu and Liu, 2024; Nie et al., 2024). These findings have spurred clinical investigations into the potential therapeutic benefits of GBE for patients with IPF.

Despite the growing body of literature on the use of GBE in IPF, there is a lack of consensus regarding its efficacy and safety (Yao et al., 2024). A systematic review and meta-analysis of the available evidence is necessary to synthesize the results of these studies and provide a comprehensive assessment of the potential benefits and risks associated with GBE treatment in IPF patients.

The protocol for this systematic review and meta-analysis has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the identifier CRD42024603534. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for reporting (Moher et al., 2015).

Our study found that GBE significantly improves the total effective rate, PaO2, SaO2, FVC, FEV1/FVC, MVV, 6MWT, IFN-γ, and decreases PaCO2, IL-4, HA, and LN in patients with IPF. These findings underscore the potential therapeutic benefits of GBE in the management of IPF.

The observed improvements in blood gas analysis parameters, particularly the increase in PaO2 and SaO2, suggest that GBE may enhance oxygenation in IPF patients, which is crucial given the impaired gas exchange characteristic of the disease (Otoupalova et al., 2020). This improvement is likely attributable to GBE’s potent antioxidant capabilities, which are believed to mitigate oxidative stress and pulmonary inflammation, consequently facilitating enhanced oxygen diffusion and utilization (Noor et al., 2022). The reduction in PaCO2 levels observed in our study may indicate improved ventilatory efficiency with GBE treatment, which could be particularly beneficial in managing the respiratory acidosis often seen in advanced IPF (Wu et al., 2022). This reduction may also indicate GBE’s beneficial impact on gas exchange and ventilation, potentially mediated through its anti-inflammatory effects, which could alleviate airway inflammation and enhance lung compliance (Tao et al., 2019).

The positive effects on pulmonary function tests, including FVC and FEV1/FVC, indicate that GBE may help to preserve or even improve lung capacity and airflow, which are typically compromised in IPF (Mori and Kondoh, 2021; Wuyts et al., 2020). Previous studies suggest that a ≥5% decline in FVC is recognized as a predictor of mortality in IPF (du Bois et al., 2011), implying that FVC improvement may represent disease stabilization. This preservation or enhancement may stem from GBE’s ability to modulate inflammatory pathways and curtail fibrosis, thereby decelerating the deterioration of lung function (Tian et al., 2018). Furthermore, The improvement in MVV and 6MWT scores further suggests that GBE may enhance the exercise tolerance and overall physical performance of IPF patients, which is closely associated with their quality of life (Mori and Kondoh, 2021; Oğuz et al., 2024). These enhancements are likely due to improved oxygenation, reduced pulmonary vascular resistance, and optimized lung function, all of which contribute to an expanded exercise capacity and elevated physical activity levels.

Inflammation plays a key role in the progression of IPF. In IPF, the Th2-type immune response, characterized by the production of IL-4, is associated with the promotion of fibrosis. IL-4 is known to activate M2 macrophages (Kokubo et al., 2022), which are involved in anti-inflammatory responses, tissue repair, and the deposition of collagen and extracellular matrix (ECM) (Spagnolo et al., 2022). The shift towards a Th2-dominant immune response in IPF is further supported by the increased levels of IL-4 observed in patients, which can lead to tissue inflammation and fibrosis (Heukels et al., 2019). IFN-γ, on the other hand, is a Th1-type cytokine that typically has anti-fibrotic effects. It can inhibit the deposition of collagen by fibroblasts, suggesting that a balance between Th1 and Th2 responses is crucial in the pathogenesis of IPF (Chang et al., 2021; Carvalho et al., 2019).

Recurrent alveolar epithelial injuries triggering the early development of fibrosis (Chambers and Mercer, 2015). These injuries, combined with dysregulated wound repair and myofibroblast dysfunction, lead to sustained tissue remodeling and fibrosis characteristic of IPF (Confalonieri et al., 2022; Younesi et al., 2024). The decrease in IL-4, the fibrosis markers HA and LN, along with the increase in IFN-γ, suggests that GBE may modulate the inflammatory and fibrotic processes in IPF. This modulation is supported by recent research indicating that GBE possesses anti-inflammatory and anti-fibrotic properties (Chummun et al., 2024; Lee et al., 2024), potentially mediated through the regulation of various signaling pathways, including TGF-β1/Smad (Liang et al., 2024).

The anti-inflammatory effects of GBE have been investigated in various studies. Gargouri et al. found that GBE has anti-neuroinflammatory effects in LPS-activated primary microglial cells, which could be relevant to its effects in IPF given the role of inflammation in the disease’s pathogenesis (Gargouri et al., 2018). Additionally, the ability of GBE to modulate cytokine production, as shown by Li et al., who demonstrated the anti-inflammatory effects of GBE components on lipopolysaccharide-stimulated RAW264.7 macrophages, further supports its potential role in reducing inflammation in IPF (Li et al., 2019).

The variability in GBE formulations across studies may influence therapeutic outcomes. As shown in Table 1, extracts varied in dosage forms (e.g., tablets, capsules) and standardization markers. Despite this variability, consistent improvements in oxygenation and fibrosis markers across most studies suggest that core bioactive components (flavonoids and terpene lactones) synergistically drive therapeutic benefits. Future trials should prioritize standardized, high-quality extracts to minimize variability and confirm dose-response relationships.

The potential relevance of our findings extends beyond IPF. Pulmonary fibrosis can also be a serious issue after SARS-CoV-2 infections and may be relevant for post-COVID-19 symptoms. The pathogenesis of post-COVID-19 pulmonary fibrosis involves inflammation and oxidative stress, similar to IPF. Given the anti-inflammatory and antioxidant properties of GBE, it may have therapeutic potential in this context. Several publications have suggested the efficacy of GBE in various symptoms related to SARS-CoV-2 infection (e.g., doi: 10.12659/AJCR.937094). Future research should explore the potential of GBE in treating post-COVID-19 pulmonary fibrosis.

While our findings suggest that GBE could be a valuable adjunct to conventional IPF therapy, it is essential to consider the study limitations. The generalizability of our findings may be limited due to the inclusion of single - center studies conducted exclusively in China, which could affect the applicability of our results to diverse populations. Moreover, the high heterogeneity observed across studies, likely attributable to variations in drug dosage forms, active ingredient content, and demographic characteristics of the study populations, should be taken into account when interpreting the results. In addition, most trials did not report all - cause adverse events or serious adverse events, which restricts the assessment of overall safety. Future studies should adhere to harmonized AE classification systems and prioritize transparency in safety data to address these limitations and provide more comprehensive and reliable evidence for the clinical application of GBE in IPF treatment.

Our study indicates that GBE may improve clinical outcomes in patients with IPF, including oxygenation, lung function, and exercise tolerance, while modulating inflammation and fibrosis markers. These findings suggest that GBE could be a valuable adjunct therapy for IPF, warranting further investigation in larger clinical trials to confirm its efficacy and safety.