Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease that leads to the formation of lung scarring. The pathogenesis of IPF involves complex interactions between various cell types and signaling pathways, and the precise triggers and exact cause of IPF are still unknown. However, studies have reported that the development of IPF begins with alveolar epithelial injury in the context of predisposing factors, such as genetics, aging, environment, epigenetics, immune response, and comorbidities. Persistent injury leads to metabolic dysfunction, senescence, abnormal epithelial cell activation, and impaired epithelial repair in alveolar epithelial cells (AECs). Dysregulated AECs interact with mesenchymal cells, immune cells, and endothelial cells through multiple signaling mechanisms [1]. Molecular abnormalities involved in a series of profibrotic cellular interactions have been identified; the affected factors include reactive oxygen species (ROS), inflammatory cytokines, pulmonary surfactants, matrix remodeling factors, growth factors, and noncoding RNAs. Various cellular processes are also thought to promote lung fibrosis; such processes include cell apoptosis, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress. These complex changes occur as a result of AEC injury, ultimately leading to the transformation of fibroblasts into myofibroblasts, excessive deposition of extracellular matrix (ECM), pulmonary interstitial fibrosis, progressive worsening of the disease, and eventually respiratory failure and death. Current treatment options for IPF have limited efficacy. Although two drugs, pirfenidone and nintedanib, approved by the Food and Drug Administration (FDA), have been reported to delay the decline in lung function in some IPF patients, the prognosis of IPF remains poor. The median survival of newly diagnosed adult IPF patients (typically over 60 years old) is less than 5 years [2]. Lung transplantation is an effective treatment option for patients with end-stage IPF, but it is limited to a relatively young and healthy subset of patients [3]. Therefore, a better understanding of the underlying systemic pathogenic factors and mechanisms involved in IPF is crucial for optimizing IPF management and treatment.

IPF has been demonstrated to be an age-related disease [4], and changes in body composition accompany the processes of aging and obesity. Alterations in the immune-metabolic characteristics of adipose tissue and the redistribution of fat have been identified as risk factors for various age-related diseases [5]. Fat tissue not only functions to regulate temperature and store energy, as recent findings have also revealed its active role as an endocrine and immune organ. Adipose-derived factors and immune cell populations within adipose tissue impact systemic immunity and metabolism. Different immune cell populations exist in adipose tissue, and their composition and immune responses vary based on nutritional and environmental conditions. Specifically, factors such as aging and obesity promote low-grade sterile inflammation within adipose tissue and excessive infiltration of immune cells. This is accompanied by a decline in the ability of adipose tissue to store lipids, leading to ectopic fat deposition (EFD). However, cold exposure resolves obesity-induced chronic inflammation [6]. Compared to subcutaneous fat, visceral adipose tissue (VAT) is more strongly associated with chronic inflammatory diseases such as coronary artery disease, nonalcoholic steatohepatitis, diabetes, and obesity. In fact, there is also increasing recognition of the relationship between VAT and various lung diseases, including IPF. The effects of excessive VAT on pulmonary diseases include its mechanical effects on the respiratory tract, lipotoxicity, pro-inflammatory properties, and oxidative stress. Recent evidence suggests that VAT could be a modifiable risk factor for IPF [7]. However, body composition analysis of IPF patients is often overlooked, and there is currently no comprehensive review on the complex relationship between fat deposition and IPF.

There is growing interest in the role of lipids in regulating the process of pulmonary fibrosis. However, whether ectopic and visceral fat deposition serves as a profibrotic factor in the development of fibrosis and as a clinically intervenable factor remains largely unknown. This review emphasizes the frequently overlooked role of fat deposition in pulmonary fibrosis and summarizes abundant basic experiments and clinical trials. This is the first review to summarize lipid-lowering drugs, hypoglycemic drugs, and lipid-targeting drugs as a therapeutic approach for pulmonary fibrosis. By using bioinformatics methods, this review reveals lipid metabolism-related genes (LMRGs) associated with pulmonary fibrosis, introduces IPF assessment tools that are easily applicable in clinical practice, and offers novel intervention approaches from a new perspective to improve fat deposition-associated pulmonary fibrosis.

Definition and causes of EFD

When adipose tissue dysfunction occurs or when the energy intake exceeds the storage capacity of subcutaneous adipose tissue (SAT), further calorie overload leads to excess lipid accumulation. Excess lipids accumulate in organs and tissues such as the liver, heart (pericardium, epicardium, and myocardium), lungs, intestines, pancreas, skeletal muscles, and blood vessels. This process is known as "EFD" [8]. One characteristic of EFD in humans is increased VAT accumulation, which is associated with abdominal obesity and is unrelated to body mass index (BMI) [8]. Obesity and aging significantly affect adipose tissue function by altering the spectrum of adipokines secreted by adipocytes, promoting adipocyte hypertrophy, changing the population and function of fibroadipogenic progenitor (FAP) cells, and increasing adipose tissue macrophage (ATM) infiltration [9]. These effects prevent SAT from proliferating and expanding to serve as a protective fat storage depot. In fact, several factors can contribute to increased fat deposition; these factors include high-fat diets, high-sugar diets, decreased physical activity, low serum albumin levels [10] (which binds and transports free fatty acids [FFAs]), male sex, and hormonal imbalance [11].

EFD in the lung induces alveolar structural and functional damage in IPF

Accumulating evidence indicates that a high-fat diet promotes lung fibrosis [12]. In obese individuals, fat can directly accumulate in the lung and airways; adipose tissue can be found in the outer walls of the larger airways, correlating with BMI, airway wall thickness, and higher neutrophil counts [13]. Studies on obese animal models have shown elevated levels of phospholipids and triglycerides in lung tissue [14]. Abundant lipid droplets can be observed in the pulmonary interstitium and lung macrophages, concomitant with the destruction of ultrastructural features of alveolar epithelial type II cells (AT2), expansion of rough endoplasmic reticulum, reduced cellular biosynthesis, impaired secretion of lung surfactant, and increased interstitial collagen [15]. Animal studies have revealed that obese diabetic rats exhibit a 136% increase in total lung triglyceride content, a 32% increase in interstitial collagen fibers, and a reduced diffusing capacity of the lungs for carbon monoxide (DLCO) [16].

EFD can also occur in lung lipofibroblasts (LIFs) of obese individuals. LIFs are important lung stromal cells that are commonly found adjacent to AT2 cells and support the self-renewal and differentiation of AT2 stem cells to AT1 cells. LIFs provide triglycerides to AT2 cells for the synthesis of pulmonary surfactant [17]. Fat deposition associated with diabetes, obesity, and aging leads to impaired function of lung LIFs, compromising their ability to aid in the renewal of AECs and maintain alveolar lipid homeostasis. Furthermore, dysfunctional LIFs can directly transdifferentiate into myofibroblasts, resulting in excessive ECM production and subsequent pulmonary fibrosis [18,19,20].

Lipotoxicity of fat deposition and IPF: direct cytotoxicity and indirect proinflammatory effectsLipotoxicity of FFAs to AECs promotes pulmonary fibrosis

The profibrotic role of pulmonary EFD is associated with the lipotoxicity of excessive fatty acids on AECs. Enlarged adipocytes also exhibit enhanced lipolysis, leading to increased delivery of FFAs to other organs. Increased FFA levels can disrupt the integrity of biological membranes in EFD tissues and alter cellular acid‒base homeostasis. FFAs have been shown to activate Toll-like receptor 2 (TLR-2), TLR-4/nuclear factor-kappaB (NF-κB), and c-Jun N-terminal kinase (JNK) signaling pathways, thereby promoting inflammation and insulin resistance [21, 22]. Furthermore, FFAs serve as precursors for the synthesis of harmful bioactive lipids, particularly ceramides and diacylglycerols. Overall, the deleterious effects resulting from the secretion of adipokines, lipid molecules, and inflammatory factors from ectopic fat tissues are referred to as "lipotoxicity."

Elevated levels of palmitic acid esters (a saturated FFA) have been observed in the lungs of patients with IPF, leading to endoplasmic reticulum stress and apoptosis in AECs. This phenomenon has been confirmed in a bleomycin (BLM)-induced IPF mouse model fed different diets [23]. The lipotoxicity of AECs induced by a high-fat diet suggests that EFD contributes to the initiation of IPF and exacerbates fibrosis severity. In addition to inducing endoplasmic reticulum stress and AEC apoptosis, lung EFD has been associated with increased lipid levels in bronchoalveolar lavage fluid (BALF) in a BLM-induced model. Alveolar macrophages engulf extracellular oxidized phospholipids and transform into lipid-laden foam cells, releasing more transforming growth factor beta1 (TGF-β1) and further exacerbating pulmonary fibrosis [24]. Lipid-lowering agents and cluster of differentiation 36 (CD36, a fatty acid translocase) inhibitors or CD36 gene knockout reduced the differentiation of lung fibroblasts to myofibroblasts in BLM mice [25, 26]. This suggests that EFD plays a crucial role in pulmonary fibrosis through macrophage-CD36 oxidative lipid signaling.

Further metabolites of FFAs, known as bioactive sphingolipids, such as sphingosine-1-phosphate (S1P), play an important role in the pathogenesis of pulmonary fibrosis [27]. Under conditions of nutrient overload, S1P synthesis increases using neural-derived sphingolipids as substrates, and S1P acts as a second messenger by autocrine or paracrine binding to G protein-coupled receptors. Studies have shown that the levels of sphingosine kinase 1 (SPHK1, catalyzing the generation of S1P) are significantly increased in IPF patient lung tissues and strongly correlated with α-smooth muscle actin (α-SMA), vimentin, and type I collagen. S1P and SPHK1 levels in BALF, serum, and peripheral blood monocytes of IPF patients are negatively correlated with lung function and positively correlated with mortality rate [28]. Animal and cell experiments have shown that the SPHK1/S1P signaling pathway is associated with TGF-β signaling, promoting the activation of fibroblasts and their transformation into myofibroblasts through the activation of mitochondrial Rho kinase, the Hippo/YAP (Yes-associated protein) pathway, etc. [29,30,31].

Mechanism of adipose-derived adipokines in pulmonary fibrosis

In addition to lipid molecules such as FFAs, adipose-derived adipokines are also considered key participants in the development of pulmonary fibrosis in IPF patients and BLM-treated mice. Changes in the secretion levels of various adipokines, including hormones (such as leptin and adiponectin) and peptides (such as angiotensinogen, apelin, resistin, and plasminogen activator inhibitor-1 [PAI-1]), have been observed in obese and elderly patients [32, 33]. Leptin and adiponectin play a role in the pathogenesis of obesity-related lung diseases by affecting systemic inflammation, regulatory T (Treg) cell activity, and T helper cell 17 (Th17) and T helper cell 2 (Th2) immune responses [34]. It is known that aging, a high-fat diet, and adipose tissue dysfunction caused by obesity increase the leptin/adiponectin ratio, which is associated with lung function and fibrosis markers [35]. Serum leptin levels are positively correlated with body fat and negatively correlated with lung function. In contrast to leptin, adiponectin levels are decreased in subjects with impaired lung function and obesity [36].

Leptin is secreted by adipocytes in white adipose tissue, and leptin receptors are highly expressed on the surface of alveolar macrophages. The binding of leptin to its receptor drives the activation of the NOD (nucleotide oligomerization domain)-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome. This leads to the production of pro-inflammatory and pro-fibrotic cytokines, such as interleukin (IL)-1, IL-18, and TGF-β, promoting AEC mitochondrial stress, cellular apoptosis, and insulin resistance [37]. Activation of the NLRP3 inflammasome is also closely associated with increased collagen deposition and enhanced expression of connective tissue growth factor in pulmonary fibrosis [38]. Increased IL-1β signaling in the lungs promotes the expression of proinflammatory cytokines (such as IL-23 and IL-5) and recruits T cells, B cells, and eosinophils to produce IL-13 and TGF-β1, which are critical regulatory factors for fibroblast activation and excessive ECM production [39]. However, VAT has a stronger negative correlation with adiponectin than subcutaneous fat [40]. Adiponectin was identified as an initiator of AMP-activated protein kinase (AMPK)-dependent autophagy.

Deficiency of adiponectin, which is associated with EFD, can lead to the generation of ROS and potassium efflux. This induces mitochondrial dysfunction and results in lung injury and activation of the NLRP3 inflammasome [41]. Adiponectin has also been identified as an anti-atherosclerotic, anti-inflammatory, and anti-diabetic adipokine, and these protective effects are attributed to its impact on the activation of the NF-kB (nuclear factor kappa B) pathway in B cells, which enhances insulin sensitivity [37, 42].

Another important adipokine is angiotensinogen (AGT), which is produced by adipose tissue and accounts for one-third of the circulating AGT levels. In the obese state, adipose tissue-produced AGT increases [43], leading to excessive activation of the local adipose tissue and systemic renin-angiotensin system (RAS) [44,45,46]. Studies have revealed that patients with the ID/DD (insertion/deletion) polymorphism of angiotensin-converting enzyme (indicating higher levels of the enzyme) are prone to pulmonary fibrosis [47]. Angiotensin II (Ang II) has been identified as a pro-apoptotic and pro-fibrotic factor in experimental pulmonary fibrosis animal models. In human lung fibroblast cultures, Ang II induces the activation of TGF-β1/Smad2/3, promoting fibroblast-myofibroblast transition [48]. Elevated Ang II levels in the local or circulation of mouse lungs can induce progressive pulmonary fibrosis, while renin inhibitors such as aliskiren or angiotensin II type 1 receptor-specific antagonists, such as losartan, can block the production of ECM proteins and fibrogenic factors [49, 50].

Similar to Ang II, the adipokine PAI-1 is also overexpressed and released by adipocytes in obesity; it has been shown to have a definite promoting effect on pulmonary fibrosis [51]. PAI-1 is a recognized inhibitor of fibrinolysis and can also affect the functionality of fibronectin, thereby interfering with cell adhesion [52]. Its overexpression contributes to the accumulation of ECM. PAI-1 is increased in the lungs of patients with pulmonary fibrosis. It not only promotes fibrosis but also activates alveolar macrophages to promote inflammation, and through TGF-β1, it strongly induces AT2 cell senescence [53]. However, it should be noted that the current research on the direct relationship among Ang II, PAI-1 sourced from excessive adipose tissues, and IPF in humans is still limited in terms of quantity. Considering that visceral fat is one of the main sources of fibrotic and inflammatory factors, further research into the mechanisms underlying the association between visceral fat and fibrosis is crucial. The changes in aging adipose tissue and the involvement of fat deposition in the occurrence and development of IPF are shown in Fig. 1.

Fig. 1

Alterations in aging adipose tissue and the involvement of fat deposition in the occurrence and development of IPF. 1) During the aging process, excessive expansion of adipose tissue leads to hypoxia. This stimulates adipocytes and ATMs to secrete inflammatory chemokines, resulting in immune cell infiltration in aging adipose tissue. 2) Fibrosis in dysfunctional adipose tissue leads to lipotoxicity and an increased leptin/adiponectin ratio. This activates highly proinflammatory M1-type macrophages (M1 ATMs) through molecules such as leptin, PAI-1, FFA, and inflammatory cytokines, thereby exacerbating the inflammatory response. 3) Lipotoxicity and inflammation in aging adipose tissue leads to endoplasmic reticulum stress, mitochondrial dysfunction, apoptosis, autophagy and necrosis of AT2 cells. Subsequently, in the alveoli, cell debris, recruited immune cells, and foam cells (macrophages engulfing lipid droplets) participate in the inflammatory cascade response, resulting in fibroblast-to-myofibroblast (MYF) transformation and epithelial-mesenchymal transition (EMT). 4) Adipose factors such as Ang II, PAI-1, and S1P can also promote fibroblast-to-MYF transformation. 5) Lipotoxicity and inflammation not only promote the differentiation of LIFs into MYFs but also affect the supply of pulmonary surfactant precursors to AT2 cells. The figure was created using BioRender (www.biorender.com). Abbreviations: adipose tissue macrophages (ATMs), plasminogen activator inhibitor-1 (PAI-1), free fatty acids (FFA), alveolar epithelial type II cells (AT2), myofibroblast (MYF), epithelial-mesenchymal transition (EMT), Angiotensin II (Ang II), sphingosine-1-phosphate (S1P), lipofibroblasts (LIFs)

Insulin resistance and immune cell infiltration in the fat deposition of lungs promote IPFInsulin resistance in fat deposition promotes IPF through TGF-β signaling

Insulin resistance caused by elevated levels of adipokines, resistin and retinol-binding protein 4 and reduced levels of adiponectin is another potential mechanism for the occurrence and development of IPF [54]. Additionally, enlarged fat cells release proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), IL-6, IL-8, and monocyte chemotactic protein-1 (MCP-1), leading to serine phosphorylation of insulin receptor substrate-1 (IRS-1) production and blocking insulin signal transduction. This consequently reduces insulin sensitivity and causes insulin resistance, which is a key feature of metabolic syndrome [55]. Compared to elderly patients without metabolic syndrome, elderly patients with metabolic syndrome have higher airway resistance. They also exhibit higher levels of proinflammatory mediators, such as leptin, IL-1β, IL-8, and TNF-α, lower levels of anti-inflammatory mediators, including adiponectin, IL-1 receptor antagonist, and IL-10, and increased expression levels of TGF-β1 and phosphorylated Smad-2/3 [35]. In mice, intranasal insulin administration enhances bronchial epithelial TGF-β1 expression, activating the TGF-β/Smad signaling pathway and causing fibrosis around the airways and blood vessels. TGF-β also stimulates the differentiation of Th0 cells into Th17 cells, which release IL-17 and contribute to airway hyperreactivity [54]. Serum vitamin D and NAD (nicotinamide adenine dinucleotide)-dependent deacetylase sirtuin (SIRT), an anti-aging factor, levels are decreased under conditions of insulin resistance. Vitamin D deficiency inhibits the phosphorylation of Smad-2/3, activates RAS activity, and subsequently activates TGF-β1 signaling, promoting pulmonary fibrosis [56]. SIRT-1 has been shown to inhibit NF-κB activity and reduce inflammation through various mechanisms, including inhibiting iNOS (inducible nitric oxide synthase) activity and downregulating COX-2 (Cyclooxygenase-2) expression, thereby alleviating oxidative stress. Aerobic exercise in obese mice improves insulin resistance, reduces neutrophil infiltration in the lungs, decreases pro-inflammatory, pro-oxidative stress, and pro-fibrotic factors in BALF, and upregulates the expression of anti-inflammatory factors IL-10 and SIRT-1 mRNA in the lungs [57]. Furthermore, studies have indicated that SIRT-1 acts as a target for anti-pulmonary fibrosis drugs and inhibits the EMT in BLM-induced pulmonary fibrosis in mice [58].

Fat deposition participates in the pathogenesis of IPF through immune cell infiltration

The presence of inflammatory cells in dysfunctional adipose tissue can affect adjacent tissues and organs [59]. As mentioned earlier, ectopic fat can be directly deposited in airways, alveolar interstitium, lung LIFs, and alveolar macrophages, indicating that the lungs can be directly influenced by inflammatory factors released from local adipose tissue and immune cell infiltration. Enlarged adipocytes and reduced capillary density in hypertrophic adipose tissue lead to a hypoxic state in adipocytes, characterized by abnormal preadipocyte differentiation, inflammation, altered secretion profile, increased oxidative stress and mitochondrial dysfunction in adipocytes, and accumulation of aged fat cells and fibrosis in adipose tissue [60]. The differentiation of preadipocytes to adipocytes is decreased, and instead, their differentiation to ATMs expressing surface markers, such as F4/80, CD80, and CD86, is increased. Moreover, adipocytes undergo hypoxic cell death, recruiting a large number of monocytes through MCP-1. These monocytes differentiate into proinflammatory M1 macrophages and form “crown-like structures,” a process activated through the NLRP3 pathway [61]. During the formation of crown-like structures, lipid metabolism increases in ATMs, leading to lipotoxicity, inflammation, and enhanced insulin resistance [62].

In obese and elderly VAT, ATMs are the most abundant immune cells. These cells account for 10% of immune cells in normal subjects and 50% of immune cells in obese individuals, and the ratio of M1 ATMs (proinflammatory characteristics) to M2 ATMs (anti-inflammatory characteristics) is significantly increased in obese individuals [63]. Hypoxia may induce inflammation through hypoxia-inducible factor 1-alpha (HIF-1α) gene expression, triggering the secretion of proinflammatory mediators such as TNF-α, IL-6, IL-8, MCP-1, adipokines, and retinol-binding protein by hypertrophic adipocytes and M1 ATMs and promoting further immune cell infiltration [64, 65]. Lymphocytes constitute the second most abundant immune cell population in the VAT of obese and elderly patients. There was a twofold increase in CD3 + T cells, predominantly CD8 + T cells (cytotoxic T cells), in aged mouse VAT compared to young animal VAT, and a similar trend was observed in obese mice [66,