One of the fundamental characteristics of cellular senescence is prolonged or permanent cell cycle arrest. Several factors, including telomere shortening, DNA damage, oxidative stress, senescence gene regulation, and epigenetic alterations, can trigger this process in IPF, ultimately limiting the regeneration of alveolar epithelial progenitor cells (Suryadevara et al., 2024). Single-cell RNA sequencing studies have shown that increased ATⅡ cell senescence in the lung tissues of IPF patients accelerates pulmonary fibrosis by activating pro-fibrotic myofibroblasts through multiple conventional mechanisms (Rubio et al., 2020). The prevailing consensus is that IPF is driven by ATⅡ senescence, which leads to myofibroblast activation and ECM synthesis, resulting in fibrotic scarring and impaired lung tissue repair (Figure 2).

ATⅡ cells play a crucial role in maintaining alveolar structure, stabilizing intrapulmonary function, and serving as the primary stem cells for alveolar repair. They can differentiate into ATⅠ cells to restore the damaged alveolar barrier. According to Witschi’s theory, lung fibrosis originates and progresses due to epithelial damage microfoci. If these microfoci are not repaired in a timely manner, the normal balance between fibroblasts and epithelial cells is disrupted, promoting fibrosis development (Haschek and Witschi, 1979).

When ATⅡ cells undergo senescence, several age-related changes occur in lung tissue, including reduced alveolar epithelial stem cell renewal, impaired ATⅡ function and differentiation capacity, defective lung tissue regeneration, increased expression of senescence markers such as p16 and p21, and altered β-galactosidase activity (SA-β-gal). The failure of senescent ATⅡ cells to maintain the alveolar barrier, coupled with cell cycle arrest, leads to fibroblast activation, proliferation, and collagen deposition, ultimately contributing to fibrotic scarring (Liang et al., 2023).

In this study, we focused on the role of ATⅡ cells in the development of IPF, their contribution to a pro-fibrotic cellular environment, their predisposition to fibrosis, and their regulation of cellular communication through SASP paracrine and autocrine signaling pathways.

Atypical lung tissue healing is triggered by the SASP, which primarily consists of growth factors, chemokines, and pro-inflammatory cytokines (Zeng et al., 2024a). Overexpression of SASP has been shown to strongly induce cellular senescence and promote epithelial-mesenchymal transition (EMT) through autocrine secretion (Chilosi et al., 2013). Additionally, SASP regulates the microenvironment in a paracrine manner, stimulating neighboring fibroblasts and myofibroblasts to excessively ECM, leading to lung tissue remodeling and, ultimately, the pathological progression of pulmonary fibrosis. Furthermore, SASP accelerates immune cell senescence and promotes chronic inflammation, which weakens immune function and impairs the clearance of inflammatory factors and senescent cells (Li et al., 2024). This creates a vicious cycle of senescence and inflammation. The immune system dysfunction caused by this cycle is referred to as immunosenescence (Dasgupta et al., 2024).

On one hand, SASP contributes to the progression of IPF through autocrine signaling. Yasunori Enomoto et al. demonstrated that DNA damage induced by bleomycin (BLM) activated p53 signaling in ATⅡ cells, leading to TGF-β-mediated pro-fibrotic gene expression. This initiated a positive feedback loop of TGF-β signaling, which further exacerbated ATⅡ senescence and contributed to IPF development (Enomoto et al., 2023).

On the other hand, SASP secreted by senescent ATⅡ cells can induce senescence in nearby cells through paracrine signaling, playing a crucial role in lung aging and the progression of pulmonary fibrosis. Lehmann hypothesized that the reprogramming of alveolar epithelial cells by SASP components—such as interleukin-6 (IL-6), interleukin-1β (IL-1β), matrix metalloproteinase-12 (MMP-12), chemokine ligand 2 (CCL2), and keratinocyte growth factor—plays a major role in the pathophysiology of IPF. Their study also demonstrated that senescent ATⅡ cells in mice with pulmonary fibrosis secrete higher levels of SASP, which in turn promotes fibroblast-to-myofibroblast transformation, thereby exacerbating fibrosis (Lehmann et al., 2017).

Furthermore, aging ATⅡ cells have been found to promote massive proliferation and activation of fibroblasts and myofibroblasts through the expression of SASP factors such as PDGF, tumor necrosis factor (TNF), endothelin-1, connective tissue growth factor (CTGF), chemokine (C-X-C motif) ligand 12 (CXCL12), and plasminogen activator inhibitor-1 (PAI-1) (Rana et al., 2020). In vitro studies by Rana T demonstrated that PAI-1 serves as both a marker and mediator of cellular senescence. Notably, PAI-1 knockdown almost completely reversed bleomycin-induced ATⅡ senescence and pulmonary fibrosis in mice (Li et al., 2023).

In conclusion, the autocrine and paracrine involvement of SASP in cellular communication disrupts lung tissue repair, leading senescent ATⅡ cells to drive the development of IPF.

In addition, telomere dysfunction plays a crucial role in the involvement of senescent ATⅡ cells in the development of IPF. A recent study demonstrated that telomerase inactivation due to TERC gene deletion not only accelerated ATⅡ cell senescence but also promoted apoptosis and differentiation of ATⅡ cells through both p53-dependent and p53-independent mechanisms (Zhang et al., 2021a). Other studies have shown that telomere dysfunction mediated by TRF1 deletion can lead to mitochondrial damage and pulmonary remodeling via the ECM, with increased expression of senescence markers observed in ATⅡ cells (Naikawadi et al., 2016).

Notably, the accumulation of DNA damage is one of the primary drivers of aging and age-related disorders. Studies have shown that YTHDC1 expression is reduced in both IPF patients and mouse models of pulmonary fibrosis, whereas YTHDC1 overexpression inhibits senescence and mitigates IPF in vitro and in vivo (Zhang et al., 2024).

These findings suggest that ATⅡ cell senescence disrupts lung tissue repair, thereby accelerating the onset of IPF. They also highlight a promising avenue for further research into the role of ATⅡ senescence in IPF progression. Targeting SASP secretion and intervening in ATⅡ cell senescence could be valuable therapeutic strategies for pulmonary fibrosis, as these approaches may help slow or prevent IPF progression at an early stage.

ATP production during aerobic respiration is closely linked to the structural and functional integrity of mitochondria. Cells utilize autophagy to remove dysfunctional mitochondria, thereby maintaining mitochondrial homeostasis and normal function (Boyman et al., 2020). However, autophagic activity declines with age (Harrington et al., 2023). Notably, 50% of lung mitochondria are found in ATⅡ cells, making them particularly susceptible to age-related changes such as mitochondrial enlargement, cristae loss, endosome degradation, and reduced respiratory capacity (Sreedhar et al., 2020). Using TEM, Xia observed a significant increase in mitochondrial vacuolization and membrane rupture in senescent ATⅡ cells (Ning et al., 2019), indicating mitochondrial dysfunction and impaired energy metabolism.

Mitochondrial dysfunction has been linked to decreased expression of PTEN-induced putative kinase 1 (PINK1), the primary regulator of mitochondrial homeostasis in vivo. Mitochondrial damage disrupts PINK1 translocation, leading to its activation on the outer mitochondrial membrane via autophosphorylation. Activated PINK1 recruits and activates the downstream autophagy protein E3 ubiquitin ligase Parkin, which enhances mitochondrial autophagy and mitigates epithelial cell senescence—an essential mechanism for limiting fibrosis (Sosulski et al., 2015). However, maintaining the PINK1-mediated autophagy pathway in senescent ATⅡ cells is challenging (Bueno et al., 2015).

Mitochondrial autophagy reduces SASP factor release and alleviates cellular senescence (Chu et al., 2024). PINK1-mediated mitochondrial autophagy has been identified as a key factor in the pathophysiology of age-related lung diseases such as COPD and IPF (Bueno et al., 2015). Increasing evidence links mitochondrial autophagy and cellular senescence to the progression of IPF in the elderly (Wei et al., 2023a). In mouse lung tissue, PINK1 knockdown in ATⅡ cells resulted in mitochondrial enlargement and dysfunction, impairing mitochondrial autophagy and increasing susceptibility to lung fibrosis (Chu et al., 2024). Thus, the regulation of mitochondrial autophagy plays a critical role in mitigating ATⅡ cell senescence and preventing senescence-associated IPF by preserving mitochondrial homeostasis.

Groundbreaking research in mitochondrial genetics has demonstrated that mitochondria release cytochrome C, a key component of the electron transport chain (ETC.), to induce apoptosis—a programmed cell death pathway distinct from cellular senescence (Victorelli et al., 2023). Mitochondria play a critical role in apoptosis regulation. Moreover, p53 activation is a pivotal step in aging. In response to various stimuli, p53 upregulates p21 to arrest the cell cycle and subsequently regulates transcriptional programs leading to apoptosis or cellular senescence (Huang et al., 2011). Senescent cells activate the p53/p21 and p16/pRb pathways, characterized by a prolonged DNA damage response (DDR). Additionally, apoptosis is primarily regulated by the Bcl-2 (B-cell lymphoma-2) protein family (Tian et al., 2024). In normal cells, Bcl-2 proteins localize to membrane structures such as the outer mitochondrial membrane (Rasmussen and Gama, 2020), where they interact with Bak and Bax (Bcl-2 Associated X protein) to prevent oligomer formation, maintain mitochondrial membrane integrity, and inhibit cytochrome C release, exerting anti-apoptotic effects (Samuel et al., 2010; Cao et al., 2023).

Mitochondrial dysfunction is a key driver of apoptosis in ATⅡ cells with IPF. The ATM/ATR or AMPK pathway, activated by mitochondrial failure (Anand et al., 2020), phosphorylates p53, stabilizing it and enhancing its transcriptional activity. p53 disrupts the balance of Bcl-2 family proteins by activating pro-apoptotic factors and inhibiting anti-apoptotic proteins, leading to cytochrome C release and the extrusion of mtDNA into the cytoplasm through BAX/BAK pores (Schubert et al., 2024). mtDNA, as a damage-associated molecular pattern, binds to DNA pattern-recognition receptors, triggering the innate immune response via the cGAS-STING pathway (Li and Chen, 2018). In vivo studies have shown that cGAS-STING activation exacerbates apoptosis in alveolar epithelial cells (Huang et al., 2022). Moreover, persistent mitochondrial damage in IPF may exceed endogenous compensatory mechanisms, leading to chronic accumulation of dysfunctional mitochondria (Kapetanovic et al., 2015).

When ATⅡ cells undergo apoptosis, pro-apoptotic proteins Bak and Bax, initially inhibited by Bcl-2, become activated, undergo conformational changes, and oligomerize on the outer mitochondrial membrane, increasing mitochondrial outer membrane permeability (MOMP) (Subas satish et al., 2024). Excessive MOMP promotes cellular senescence, triggering inflammation and SASP molecule secretion, including IL-6 and IL-8 (Victorelli et al., 2023; Garciaz et al., 2022).

ATⅡ cells from IPF patients exhibit mitochondrial dysfunction and impaired autophagy (Bueno et al., 2015). In vivo studies have shown that PINK1-deficient mice develop similar mitochondrial abnormalities in ATⅡ cells, leading to apoptosis and lung fibrosis (Bueno et al., 2015). Additionally, persistent stress can amplify mitochondrial damage (Schuliga et al., 2021). Mitochondrial dysfunction has been reported in IPF, connective tissue disease-associated interstitial lung disease (ILD), and experimental ILD models (Pokharel et al., 2024).

Senotherapeutics aim to address aging-related health issues by eliminating or suppressing senescent cells. This approach includes two main strategies: senolytics and senomorphics (Table 1). Senolytics induce apoptosis in senescent cells by targeting anti-apoptotic pathways. For example, ABT-263 (Zhu et al., 2016) and ABT-737 (Yosef et al., 2016) bind to BCL-2, BCL-XL, and BCL-W, triggering apoptosis in senescent cells. Another senolytic, ABT-263, specifically inhibits BCL-2 and BCL-XL, effectively eliminating senescent cells. In vitro and in vivo studies confirm its anti-aging and anti-fibrotic properties, suggesting potential for treating age-related fibrotic diseases. Dasatinib (D) and quercetin (Q), when combined (D + Q), selectively induce apoptosis in senescent human cells without affecting non-senescent cells. This combination was the first identified anti-aging drug and has shown promise in improving age-related conditions in mice and in limited human trials (Justice et al., 2019).

Recent studies suggest that roxithromycin inhibits senescence through a NOX4-dependent mechanism, making it a potential treatment for IPF (Zhang et al., 2021b). However, researchers caution against its immediate use as a senolytic due to concerns about antimicrobial resistance. Instead, its properties could inform the development of future senolytic drugs. Another promising compound, senescence-specific killing compound 1 (SSK1), is activated by β-gal and removes senescent cells via p38/MAPK signaling. In vivo and ex vivo studies demonstrate its ability to alleviate IPF, reduce inflammation, and decrease senescence-related gene expression (Cai et al., 2020). Additionally, research on grape seed extract led to the successful isolation of proanthocyanidin C1, which has been shown in cellular and animal studies to effectively eliminate senescent cells and potentially extend lifespan.

Senomorphics, a newer anti-aging approach, mitigate the harmful effects of senescence by inhibiting SASPs rather than directly eliminating senescent cells. Representative senomorphics include metformin, rapamycin, and resveratrol (Wang et al., 2017; Menicacci et al., 2017; Noren hooten et al., 2016). Other potential senomorphics include aspirin, NF-κB inhibitors, p38 MAPK inhibitors, JAK/STAT inhibitors, ATM inhibitors, and statins (Bode-Böger et al., 2005). Unlike senolytics, senomorphics primarily target SASP to prevent the paracrine/autocrine spread of senescence to neighboring and distant cells.

Rapamycin, for example, has demonstrated therapeutic effects on IPF in both in vivo and ex vivo studies by inhibiting the mTOR pathway, thereby reducing SASP production and inflammation while slowing cellular senescence (Chrienova et al., 2022). Similarly, rutin, a natural compound, has been identified as a potential senomorphic that suppresses SASP expression and may be used to treat aging-related diseases (H. Liu et al., 2024).

By targeting the initial senescent cells, senomorphics not only prevent senescence from spreading but also disrupt the cycle that promotes further accumulation of senescent cells. While generally less potent than senolytics, natural polyphenols are gaining popularity due to their low toxicity and availability.

The complex nature of mitochondrial dysfunction and its elusive phenotypic thresholds make it challenging to fully understand its role in disease. However, mitochondria remain key targets for therapeutic intervention. Mitochondrial failure contributes to pulmonary fibrosis by driving ATⅡ cell senescence. Given this, targeting mitochondrial dysfunction offers a promising strategy to treat or delay IPF progression. Advances in mitochondrial biology have led to new therapeutic approaches, though human clinical trials remain limited, highlighting the need for further research. Potential treatments include antioxidants and drugs that enhance mitochondrial ATP production, reduce oxidative stress, and improve mitochondrial function (Wal et al., 2024). These strategies range from dietary interventions addressing nutritional deficiencies to pharmacological therapies that modulate mitochondrial dynamics, boost biogenesis, and mitigate oxidative damage (Table 2).

Reducing mitochondrial oxidative stress is a critical therapeutic goal. Inhibitors of mitochondrial fission play a key role in achieving this (Qi et al., 2013; Yang et al., 2024; Ko et al., 2021). Mdivi-1, for example, counteracts excess ROS by blocking Dynamin-Related Protein 1 (DRP1) GTPase activity, improving endothelial function and reducing inflammation in animal models (Qi et al., 2013). Similarly, the peptide P110 enhances mitochondrial function by inhibiting DRP1 (Qi et al., 2013). Senegenin has been shown in vivo to prevent oxidative stress-induced epithelial cell senescence and reduce lung fibrosis by modulating the Sirt1/Pgc-1α pathway (Zeng et al., 2024b). In BLM-induced lung fibrosis models, TH5487 reduced oxidative stress, promoted PINK1/Parkin-mediated mitophagy, and alleviated mitochondrial dysfunction. Additionally, clinical research indicates that MitoQ scavenges free radicals, protecting cells from oxidative stress and enhancing cellular function.

Mitochondrial autophagy (mitophagy) plays a vital role in mitigating pulmonary fibrosis caused by ATⅡ cell senescence. Tetrandrine (TET) has been shown to reduce lung inflammation and fibrosis by regulating mitophagy through the PINK1-Parkin signaling pathway (Chu et al., 2024). In MLE-12 cells, TET rescued impaired BLM-induced mitophagy by preventing the reduction of autophagy-related protein expression, while PINK1 gene knockdown abolished its effects (Chu et al., 2024). Naringenin has also been found to regulate mitophagy and alleviate pulmonary fibrosis via the ATF3/PINK1 pathway (Wei et al., 2023b). Several natural compounds, including spermidine, resveratrol, and urushiol A, support mitochondrial integrity by stimulating mitophagy and promoting biogenesis (Palikaras et al., 2018).

The cGAS/STING pathway is closely linked to aging and lung fibrosis, though its precise role remains unclear. Recent studies indicate that urushiol A-induced mitophagy reduces free cytoplasmic mtDNA activation of cGAS/STING, improving mitochondrial function. Additionally, homopalol enhances SIRT3 deacetylation activity, activating SOD2’s antioxidant function and OGG1-mediated DNA repair. This modulation of the cGAS/STING pathway helps prevent fibrosis and cellular senescence (Wu et al., 2024). Other compounds, such as purple salvia terpene ether and salvia divinorum extract, have been shown to reduce BLM-induced lung fibrosis by inhibiting TGF-β1 signaling, oxidative stress, and collagen deposition (M. Zeng et al., 2024). Harmine has been confirmed in vitro to prevent pulmonary fibrosis by regulating DDR-associated genes and activating the TP53-Gadd45α pathway (Gong et al., 2024).

Targeting inflammation linked to mitochondrial outer membrane permeabilization (miMOMP) may also be beneficial. For example, BAX inhibitor BAI-1 reduces mitochondrial BAX and BAK nanopores, lowering systemic inflammation and extending healthy lifespan in aged mice (Victorelli et al., 2023). Additionally, MitoTam, a mitochondria-targeted tamoxifen currently in clinical trials, has been shown to induce apoptosis in senescent cells and reduce senescence markers (p21 and p16) in the kidneys and lungs of aged mice (Hubackova et al., 2019).

Gene replacement therapy and gene editing technologies offer potential solutions for inherited mitochondrial disorders, though a deeper understanding of the mitochondrial genome is required. Combination therapies have also gained attention; for instance, combining MitoQ with senolytics may enhance mitochondrial function while reducing senescent cell burden.