Pulmonary fibrosis is a chronic and progressive lung disease with high morbidity and a median survival of 3–5 years after diagnosis [1]. Multiple factors increase the risk of pulmonary fibrosis, such as aging, genetic factors, and occupational or environmental exposures [2]. Notably, the SARS-CoV-2 virus, which caused the global corona virus disease 2019 (COVID-19) pandemic, initially infects and injures the respiratory system, which in turn exhibits an extensive fibrotic burden in the lung tissues [3]. Although pirfenidone and nintedanib have been approved for the clinical treatment of pulmonary fibrosis, neither drug has significantly improved survival rates, and both are associated with notable side effects [4], [5]. Therefore, there is a critical need to develop effective therapeutic drugs to treat pulmonary fibrosis.

The pathogenesis of pulmonary fibrosis involves recurrent alveolar epithelial cell injury, inflammation, epithelial-mesenchymal transition (EMT), fibroblast activation, and aberrant extracellular matrix (ECM) deposition [6]. Interleukin-23 (IL-23) is a pro-inflammatory cytokine of the IL-12 cytokine family, composed of p19 and p40 subunits. Recent studies have demonstrated that IL-23 plays a significant role in multiple inflammatory disorders, such as psoriasis, psoriatic arthritis, and inflammatory bowel disease [7]. Similarly, targeting the IL-23 pathway has been proposed as a potential therapeutic strategy for respiratory diseases. Clinical studies have found that elevated serum IL-23 levels are closely associated with chronic obstructive pulmonary disease (COPD) progression and may serve as a potential biomarker for assessing COPD [8]. Previous study has revealed that the suppression of IL-23 with a monoclonal blocking antibody attenuated lung oxidative stress, inflammation, and cellular apoptosis in cigarette smoke-induced murine emphysema [9]. Notably, IL-23 signaling is inextricably linked to adenosine 5′-triphosphate (ATP) in many inflammatory diseases [10]. As an ATP-driven proton pump, vacuolar-type H+ adenosine triphosphatase (V-ATPase) is mainly involved in maintaining intracellular acid-base balance and regulating extracellular signal transduction [11]. ATP6V0D2 (ATPase H+ Transporting V0 Subunit D2) is one of the key subunits of V-ATPase, especially well-investigated in cancer, osteoporosis, and metabolic diseases [12], [13], [14]. ATP6V0D2-deficient mice exhibited enhanced inflammatory cell infiltration in an ovalbumin-induced asthma model [15]. Furthermore, maintaining V-ATPase activity in mice could effectively ameliorate cardiac inflammation and fibrosis caused by lipid overload [16]. Thus, IL-23 and ATP6V0D2 play a critical role in the respiratory system, especially their association in the process of pulmonary fibrosis, which may move towards precision medicine for respiratory diseases.

Natural stilbenes, with a 1,2-diphenylethylene skeleton, exhibit broad bioactivities, including anti-inflammatory, anti-diabetic, neuroprotective, anti-cancer and antibacterial properties [17]. Pterostilbene (PTE) is a natural stilbene originally isolated from Pterocarpus indicus willd., and is also predominantly found in grapes and blueberries. The therapeutic potential of PTE and its health benefits make it a promising candidate drug for a wide range of diseases, including diabetes, cancer, cardiovascular disease, and neurodegenerative disorders [18], [19], [20]. PTE has robust pharmacodynamic features, such as better intestinal absorption, elevated hepatic stability, higher bioavailability and reduced toxicity compared to other stilbenes [21]. Our previous study also demonstrated that dietary supplementation with PTE could prevent alcohol-induced liver injury, regardless of acute or chronic exposure [22]. Moreover, PTE ameliorated thioacetamide-induced hepatic fibrosis by inhibiting fibrogenesis and inflammation through modulating the crosstalk between Sirt1 and STAT3 [23]. Therefore, PTE may have potential pharmacological activity for the therapy of pulmonary fibrosis, and further research would be beneficial for the development of functional supplements to treat and prevent pulmonary fibrosis.

Damaged alveolar epithelial cells release various inflammatory mediators that promote inflammatory cell infiltration and activate fibroblasts, driving the development of fibrosis [24]. Under normal conditions, fibroblasts maintain the structure of ECM in tissues. However, fibroblasts are activated and transformed into myofibroblasts, accompanied by excessive synthesis and secretion of ECM components, leading to pathological fibrosis of lung tissue [25]. The local microenvironment, composed of alveolar epithelial cells and fibroblasts, collectively promotes the occurrence and development of pulmonary fibrosis [26]. Therefore, the current study aimed to reveal that PTE regulated the IL-23/ATP6V0D2 pathway to suppress inflammatory responses, EMT, and ECM deposition. Compared with previous studies that mainly focused on single cell types, this study focused on intercellular interactions and alveolar microenvironment remodeling in pulmonary fibrosis. Further, the present study provided more theoretical support for the development and application of PTE as a functional food or clinical therapeutic drug.