Fibrosis is a pathophysiological process that afflicts numerous organs, often culminating in organ failure [1], [2]. Notably, pulmonary fibrosis (PF) poses a significant threat to respiratory function, characterized by distressing symptoms such as a persistent dry cough and progressively debilitating dyspnea [3], [4], [5]. It is worth noting that since December 2019, PF has emerged as a critical clinical hallmark of COVID-19 [6]. At present, the foremost pharmacological interventions for PF are nintedanib [7] and pirfenidone [8]. These medications are recognized for their anti-inflammatory and anti-fibrotic properties, with nintedanib acting as a small-molecule inhibitor of tyrosine kinase and pirfenidone as a novel pyridone derivative [9]. Although these medications exhibit the capacity to attenuate the progression of PF, they fall short of conferring complete protection against mortality. Consequently, the pursuit of more efficacious medications is of paramount importance for the effective management of PF.

Pharmacological research has shifted the attention towards exploring traditional Chinese medicine (TCM) formulas to combat PF. Recent studies demonstrated that TCM formulas including XuanFei Baidu [10], Jiegeng [11], and Qingfei Paidu Decoction [12] could be candidates for the treatment of PF. Qingkailing Granule (QKL), a TCM formulation, is composed of three herbal components, including Isatis tinctoria L. (Isatidis Radix), Lonicera japonica Thunb. (Lonicerae Japonicae Flos), and Gardenia jasminoides J.Ellis (Gardeniae Fructus), along with two animal-derived ingredients, Concha Margaritiferallsta and Cornu Bubali, as well as three bioactive compounds, namely baicalin (BA), cholic acid (CA), and hydeoxycholic acid (HA). Concha Margaritiferallsta and Cornu Bubali are traditionally used for clearing heat, detoxifying, and calming the mind [13]. Some researchers corroborated the antipyretic and anti-inflammatory effects of the herbal components in QKL, such as Isatis tinctoria L. [14], Lonicera japonica Thunb. [15], and Gardenia jasminoides J.Ellis [16]. These herbs, rooted in traditional applications for clearing heat and detoxification, demonstrate their potency in mitigating inflammatory responses. Notably, QKL exhibits the capacity to alleviate hallmark symptoms of PF, including chronic cough and dyspnea [17]. However, the precise impact of QKL on PF, as well as the underlying mechanisms of its action, remain to be fully elucidated.

Network pharmacology serves as the linchpin linking traditional Chinese medicine (TCM) compounds with specific diseases, providing a foundational and benchmarking platform for contemporary TCM research endeavors [18] This powerful approach enables the identification of potential active compounds from the vast array of TCM ingredients and facilitates the discernment of target proteins and the associated pathways for particular diseases [19]. Notably, TCM formulations exhibit a greater degree of complexity in comparison to individual herbal medicines, making the application of network pharmacology a pivotal tool for streamlining and simplifying intricate formulation systems [20]. Consequently, the adoption of network pharmacology is indispensable and indeed pragmatic for the prediction and validation of target proteins and mechanistic insights related to the action of QKL in the context of PF.

The amalgamation of network pharmacology analysis and experimental validation has emerged as a widely embraced approach for uncovering the effects and fundamental mechanisms underlying TCM formulations. In this study, we embarked on an investigation to elucidate the protective effects and action mechanisms of QKL and the primary bioactive compounds within bleomycin-, and TGF-β1-induced PF models. This comprehensive approach, harmonizing network pharmacology analysis with empirical experimentation, endeavors to forge a solid foundation for a more profound comprehension of TCM's potential in combating fibrotic disorders.