Vitamin A, derived from carotenoid pigments in nature (known as provitamin A), belongs to the class of fat-soluble micronutrients and undergoes two consecutive oxidation reactions to convert into its primary biologically active derivatives, retinal and retinoic acid (RA). Vitamin A serves multiple crucial functions within the human body, encompassing cell proliferation and differentiation, vision, immunity, and embryological development (21–25). Moreover, it has been proved to be intricately associated with numerous respiratory defense mechanisms and assumes a pivotal role in upholding the structural integrity of respiratory mucosa (26, 27). Vitamin A is also necessary for maintaining alveolar structure and tissue regeneration, and trophic vitamin A deficiency (VAD) leads to detrimental histological alterations in lung parenchyma which predispose to severe tissue dysfunction and respiratory diseases, even increasing the incidence and morbidity of patients, suggesting that vitamin A plays an important role in adult lungs (28–30).

The excessive deposition of ECM is widely recognized as the primary characteristic of pulmonary interstitial fibrosis. Pathological changes in lung tissue induced by VAD encompass alterations in both the content and distribution of ECM proteins (31–33). Retinoid signaling directly or indirectly modulates gene promoters, thereby participating in the regulation of ECM protein expression and influencing the expression of ECM receptor proteins on cell membranes (34). Guillermo et al. observed elevated levels of collagen I and collagen IV in vitamin A-deficient rat lungs, accompanied by a nearly twofold increase in alveolar basement membrane thickness and ectopic deposition of collagen I protein, while treatment with retinoic acid reversed these alterations (35). The mechanism underlying the alteration of ECM by VAD remains elusive, but there is some evidence. Dysregulation of transforming growth factor-β1 (TGF-β1)/Smad3 signaling pathway is considered to play a central role and is associated with bleomycin-induced pulmonary fibrosis (36). Additionally, Chiharu et al. reported all-trans retinoic acid (ATRA) inhibits both proliferation and transdifferentiation of lung fibroblasts through downregulating TGF-β expression and suppressing the IL-6/IL-6R system (IL-6 stimulates lung fibroblast proliferation in a dose-dependent manner), thereby preventing radiation- and bleomycin-induced pulmonary fibrosis in mice (37). Inhibition of IL-6 and TGF-β production by ATRA was achieved by blocking the PKC-δ/NF-κB and p38MAPK/NF-κB pathways (38) and shifting the regulatory T/T helper 17 ratio and reducing the secretion of IL-17A (39). Vitamin A also affects the EMT process of lung epithelial cells, the effect of retinoic acid in inhibiting this process has been demonstrated (40, 41). In lungs of VAD rats, there is an increased level of N-cadherin protein accompanying decreased levels of E-cadherin and β-catenin (42). Supplementation with ATRA improves alveolar septal defect at the tissue level and promotes alveolar epithelial recovery (43). All these findings collectively suggest a potential association between vitamin A and EMT process in lung fibrosis.

Patients with lung fibrosis exhibit an elevated oxidative burden and heightened levels of reactive oxygen species (ROS) generated by inflammatory cells in lungs (44, 45). ROS have been demonstrated to activate transcription factors, such as AP-1, thereby inducing the synthesis of fibrogenic factor TGF-β, various ECM proteins, as well as type I and type IV collagens (46–48). Early research on the antioxidant properties of vitamin A came from Monaghan & Schmitt, who found that dissolving fresh vitamin A in linoleic acid hindered the absorption of oxygen by linoleic acid, and this effect faded away as vitamin A was oxidized (49). Burton and Ingold proposed that beta-carotene (which is converted into vitamin A in body) and other carotenoids may play an important role in protecting tissue lipids against peroxidation in vivo (50). Both carotenoids with provitamin A activity and non-vitamin A carotenoids exert antioxidant functions in lipid phases by quenching free radicals or O₂ (51). Vitamin A and its metabolites have been frequently recognized as notable antioxidants in various tissues, including the lung, liver, and heart (52). Levels of retinol, one of the forms of vitamin A, are elevated in the bronchoalveolar lavage fluid of patients with IPF, and this increase may be part of an adaptive response to oxidative stress (14). Another study proved that VAD can disrupt the balance between ROS production and antioxidant defense mechanisms in lungs (31, 53). The above information suggests a potential association between vitamin A and pulmonary fibrosis through the redox pathway. However, experimental confirmation is required to determine whether vitamin A supplementation can effectively ameliorate pulmonary fibrosis via modulation of the redox pathway. It is worth noting that long-term excessive intake of vitamin A may disrupt the immune balance of the body (24, 54, 55). In the occurrence and development of pulmonary fibrosis, the imbalance of the immune system is an important factor (56). It is speculated from this that excessive intake of vitamin A may alter the functions and activities of immune cells, which indirectly aggravates pulmonary fibrosis.

Vitamin B refers to a group of eight water-soluble vitamins that play crucial roles in cellular metabolism. Except for vitamin B3 (niacin), which can be partially synthesized in the human body from tryptophan, the other vitamins in this group cannot be synthesized by the body and must be obtained through dietary sources. All eight components: vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin or niacinamide), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), vitamin B7 (biotin), vitamin B9 (folic acid) and vitamin B12. Each individual component of vitamin B possesses its own distinct structure and exerts unique physiological functions within the human body.

Vitamin C, scientifically referred to as ascorbic acid, is an indispensable micronutrient and a coenzyme that potentiates the activity of diverse enzymes, contributing to the immune response and the development of nervous system in humans (79, 80). Severe deficiency of vitamin C can lead to the occurrence of many serious diseases. Due to the limited ability of organisms to preserve this essential nutrient, continuous intake is necessary to prevent deficiencies. Study has shown that silicosis patients exhibit reduced serum levels of vitamin C compared to individuals not exposed to silica (81). In studies investigating the efficacy of vitamin C treatment for pulmonary fibrosis, Vildan et al. demonstrated that vitamin C did not yield significant improvements in IPF symptoms in a rat model (82). However, other studies showed that administration of vitamins C and E both alleviate fibrotic damage in lung tissue, and with a more pronounced effect observed when these two vitamins are combined in rat models (83). Furthermore, the administration of vitamin C has been shown to protect against collagen I and α-SMA deposition (84). In general, the anti-pulmonary fibrosis effect of vitamin C is primarily manifested in three aspects: anti-oxidation, anti-cell death and anti-inflammation.

Vitamin D is widely distributed throughout the body, not only in the liver but also in various tissues. Numerous hydroxylases have been discovered in these tissues, facilitating the conversion of vitamin D to 1,25-dihydroxyvitamin D. This active form is believed to exert its primary function by binding to the ligand-dependent transcription factor known as the vitamin D receptor (VDR) (128–131). Vitamin D deficiency is a prominent characteristic of physiological aging, with its concentration declining as individuals age (132). Emerging research indicates that vitamin D insufficiency exacerbates cellular aging across various cell types. Supplementation with vitamin D has conventionally been postulated to mitigate the aging process in bone and muscle cells, thereby preserving or even enhancing their overall health (133–135). Vitamin D deficiency is strongly associated with various lung diseases, including asthma and chronic obstructive pulmonary disease (COPD). Low levels of 25-hydroxyvitamin D may contribute to the development or exacerbation of these conditions (136). Furthermore, there is evidence supporting a link between vitamin D deficiency and pulmonary fibrosis. For instance, Zhou et al. found that lung Sirt1 and serum vitamin D levels declined during physiological aging, thus activating the TIME signaling pathway, and promoting senescence-associated pulmonary fibrosis (137). Li et al. discovered that vitamin D deficiency aggravated bleomycin-induced pulmonary fibrosis (138). Notably, in this study, vitamin D appears to influence the development of pulmonary fibrosis through multiple biological pathways: vitamin D deficiency not only exacerbates the lung inflammation caused by bleomycin (similar to the effect observed in the case of vitamin C deficiency), but also increases the likelihood of the occurrence of EMT in the lungs, and these are all crucial steps in the pathogenesis of pulmonary fibrosis. Additionally, it exacerbates pulmonary fibrosis by activating the TGF-β/smad3 pathway (138). Furthermore, several small-scale prospective studies have consistently demonstrated a prevalent insufficiency or deficiency of plasma vitamin D levels in patients with IPF, which is strongly correlated with acute exacerbations of the disease (139, 140). However, it should be noted that there remains a dearth of large-scale randomized controlled trials investigating the potential role of vitamin D supplementation in improving IPF outcomes.

Conversely, vitamin D supplementation has demonstrated the potential to enhance pulmonary function and impede fibrosis progression. Studies have indicated that the inhibitory effect of vitamin D on pulmonary fibrosis manifests across various stages of disease advancement. (1) In the early stage, vitamin D plays an anticoagulant role. Epithelial cells undergo damage and subsequently release inflammatory mediators that activate the anti-fibrinolytic coagulation cascade. Furthermore, studies have revealed that the overactivation of the clotting cascade permeates the entire process of pulmonary fibrosis (141, 142). Coagulation factors are mainly mediated by protease activating receptors (PARs) (141). PARs mediate tissue factor TF, which then works with activating factor VIIa (FVIIa) to form the TF/FVIIa complex (the main promoter of the clotting cascade), and this pathway can be blocked by TFPI, a protease inhibitor (143, 144). Studies have shown that vitamin D may interfere with the above clotting response in two ways: Vitamin D inhibits TF expression through TNF-α (145–147); Vitamin D is potentially involved in the regulation of TFPI expression, as several studies have demonstrated a positive correlation between their levels (146). (2) Excessive inflammatory mediators trigger the infiltration of inflammatory cells, which then release a multitude of cytokines, such as transforming growth factors and fibroblast growth factors. These released factors, in turn, promote both inflammation and fibrosis (148–150). Previous studies have shown that inflammatory mediators play an important role in the occurrence and development of pulmonary fibrosis. Vitamin D has been shown to reduce serum levels of inflammatory cytokines, including IL-3 (151), IL-17 (151, 152), IL-1, IL-6, IL-8, and TNF-α (153), and may directly act on CD4⁺ T cells to promote the secretion of the anti-inflammatory cytokine IL-10 by T regulatory cells (Tregs), controlling the further expansion of the inflammatory response (151, 152, 154, 155). (3) The activation of the EMT process by TGF-β plays a pivotal role in the pathogenesis of pulmonary fibrosis. TGF-β binds to type I and II serine/threonine receptor kinases on the cell surface, leading to the phosphorylation of SMAD2 and SMAD3. Subsequently, the phosphorylated receptor kinases are released into the cytoplasm where they form a complex with SMAD4 before translocating into the nucleus. Once inside, this activated Smad complex binds to specific Smad binding elements within the genome to execute its regulatory function, such as modulating fibrin expression (156, 157). Studies have shown that vitamin D can inhibit TGF-β-Smad signaling pathway (156, 158–160) through the specific process of 1,25(OH)₂D₃ binding complex with VDR, which directly interacts with SMAD3 to reduce the binding of SMAD3 to DNA, and ultimately inhibit TGF-β-Smad signal transduction (161, 162). In fact, it has been repeatedly demonstrated that 1,25(OH)₂D₃ interferes with the pro-fibrotic effects of TGF-β, which could in fact be predicted because calcitriol itself inhibits collagen synthesis in cells (163, 164). Moreover, vitamin D can also block the expression of several matrix metalloproteinases in alveolar macrophages and monocytes and participate in airway remodeling, which helps to reduce the excessive degradation and abnormal remodeling of the extracellular matrix, thus playing a protective role in the airways (165, 166). Additionally, vitamin D can reduce the proliferation of lung fibroblasts through the TGF-β pathway, thus playing a role in inhibiting pulmonary fibrosis (165, 167). Other studies have shown that vitamin D concentrations were positively associated with improvements in lung function, including ΔFEV1(%), ΔFVC(%), and ΔDLCO-SB(%) (166). Additionally, the presence of severe muscle weakness in individuals with IPF is associated with an elevated risk of mortality and disease severity due to cachexia or sarcopenia (168, 169). Previous studies have demonstrated the efficacy of vitamin D supplementation in enhancing muscle strength among patients afflicted with pulmonary disorders (170, 171).

The report of the Institute of Medicine (IOM) of the United States in 2011 not only discussed the upper limits (ULs) of the intake of high-dose vitamin D preparations during acute and short-term administration within a limited time period, but also emphasized the long-term administration of vitamin D. Acute toxicity may occur when the dose of vitamin D exceeds 10,000 international units per day, which will cause the serum 25(OH)D concentration exceeding 150 ng/ml (>375 nmol/L). This level is significantly higher than the upper limit of 4,000 international units per day recommended by the IOM. Taking a dose of more than 4,000 international units of vitamin D per day for several years may lead to the serum 25(OH)D concentration being in the range of 50 to 150 ng/ml (125 to 375 nmol/L), which may have potential chronic toxicity (172). Due to the high prevalence of vitamin D deficiency secondary to exocrine pancreatic insufficiency, it is a common practice to supplement vitamin D in the population of patients with cystic fibrosis. Thomas et al. conducted a retrospective analysis of the medical records of all cystic fibrosis patients followed up at the Cliniques universitaires Saint-Luc over the past 10 years. The results showed that in this high-risk population, the number of cases of excessive vitamin D intake and toxicity increased due to dosage errors in the preparation of magistral liposoluble vitamin preparations. The serum vitamin D levels of 5% of the patients indicated excessive vitamin D intake, and another 2 patients developed severe hypercalcemia (173).

Vitamin E encompasses a group of antioxidant fat-soluble vitamins, including α-, β-, γ- and δ-tocopherol as well as α-, β-, γ- and δ-tocotrienols, of which α-tocopherol stands out as the most biologically active form of vitamin E (174). The role of vitamin E in pulmonary fibrosis seems to be controversial, however, certain reports have suggested its inhibitory effect on this condition. Similar to vitamin C, vitamin E also has potent antioxidant properties that directly inhibit ROS formation in radiation fibrosis patients (82). Dietary supplementation of vitamin E significantly reduced the extent of TGF-β1, collagen deposition and histological damage following intratracheal amiodarone administration (175), and vitamin E reduced amiodarone-induced cytotoxicity in pulmonary cells, whereas other antioxidant treatments were ineffective (176). Dietary vitamin E supplementation enables rapid vitamin accumulation in lung tissue and mitigates amiodarone-induced elevation of TGF-β and hydroxyproline levels, thereby preventing lung tissue damage. Another recent study demonstrated that vitamin E significantly attenuates bleomycin-induced pulmonary fibrosis by improving mitochondrial structure and function, modulating iron metabolism, reducing inflammation (significantly reducing the transcriptional levels of interleukin-6 (Il-6), interleukin-33 (Il-33), chemokine ligand 5 (Ccl5) and TNF-α, as well as inhibiting the fibrotic effects on epithelial cells and fibroblasts (177). However, Card et al. point out that although dietary supplementation also significantly increased lung mitochondrial vitamin E content, it did not ameliorate the mitochondrial respiratory depression and disruption of mitochondrial membrane potential caused by amiodarone (178).

The role of vitamin E in cystic fibrosis disease remains a subject of intense debate within current research. In theory, vitamin E is involved in protecting the airways from oxidative stress and inflammation. Previous studies have demonstrated a decline in serum α-tocopherol levels during lung deterioration, which subsequently returned to normal following intravenous antibiotic treatment (179–181). Even within the normal range, reduced serum levels of vitamin E are associated with an elevated incidence of lung deterioration in cystic fibrosis (179). It can be inferred that low serum α-tocopherol levels may be attributed to pulmonary inflammation rather than dietary vitamin E deficiency. Therefore, the degree of chronic pulmonary inflammation should be considered when studying the relationship between pulmonary fibrosis and serum α-tocopherol. However, in a single-walled carbon nanotube-induced pulmonary fibrosis animal experiment, the researchers found that dietary vitamin E deficiency increased lung inflammation and oxidative stress. After feeding mice a vitamin E-adequate and a vitamin E-deficient diet, the researchers found that the vitamin E-deficient mice showed a 90-fold decrease of α-tocopherol in lung tissue, and a significant decrease of antioxidants and increased inflammatory response (182). However, Woestenenk et al. found that serum α-tocopherol deficiency was also rare in a large sample of children and adolescents with cystic fibrosis, although the actual vitamin intake was lower than recommended, and the study did not find a protective effect of higher serum α-tocopherol on lung function in patients with cystic fibrosis (183). The study further notes that the recommended amount of vitamin E supplementation for cystic fibrosis patients in both Europe and North America is higher than needed to prevent deficiency, and may even lead to abnormal vitamin E levels (183). Supplementation of vitamin E exceeding 400 mg/day in patients with cystic fibrosis has demonstrated deleterious effects, including an elevated risk of mortality in adults (184) and occurrence of hemorrhagic stroke (185).

Acute exacerbations of IPF are characterized by histopathological features of diffuse alveolar damage (DAD) or hemorrhage (DAH), and studies have found that vitamin K deficiency exacerbates DAH symptoms (186–188). In addition, another study showed approximately 29% of individuals under the age of 18 with cystic fibrosis exhibit diminished levels of vitamin K (189). The risk of clinically relevant vitamin K deficiency is heightened by various factors, such as the use of oral anticoagulants or antibiotics, as well as reduced intestinal vitamin K uptake for multiple reasons, such as fat uptake inhibitors (190). Janssen R. proposed that vitamin K deficiency is one of the potential sources of pathogenesis of IPF. This proposition builds on Booth and colleagues' finding that there is a significant increase in vitamin K-dependent matrix Gla protein (MGP) expression in the lungs of IPF patients, indicating potential vitamin K deficiency (191). Vitamin K plays an important role in preventing tissue degeneration caused by the hardening or degradation of elastin and collagen (192). The vitamin K-activated MGP possesses the capability to penetrate the interior of elastin and collagen fibers, thereby playing a pivotal role in safeguarding ECM proteins against mineralization (193). Growth arrest-specific 6 (GAS6) and protein S are also vitamin K-dependent proteins, which are important regulators of tissue repair after injury and may be involved in the pathogenesis of pulmonary fibrosis (194). In addition to anticoagulant effects, protein S also has a protective effect on lung fibers through anti-apoptotic properties (195). Therefore, assessing the vitamin K status of individuals with pulmonary fibrosis and providing tailored dietary recommendations to enhance their vitamin K levels could potentially serve as a valuable intervention strategy, particularly for those who frequently experience infections (requiring antibiotic treatment) while concurrently using anticoagulant medications.

Since the primary deficiency disease associated with vitamin K is bleeding due to impaired blood clotting, it is commonly believed that high intake of vitamin K may increase the risk of thrombosis. However, in fact, excessive intake of vitamin K does not lead to more carboxylation of clotting factors. Even when monitored with the most sensitive technique (endogenous thrombin potential, ETP), an increased tendency to thrombosis has not been found in any of the participants (196). At present, there is a lack of evidence on whether high intake of vitamin K has an adverse effect on patients with pulmonary fibrosis.