AEC2s are the lung’s chief surfactant-producing, lipid-metabolizing cells (Wasnick et al., 2023). They secrete a lipoprotein surfactant (∼90% lipid, rich in phosphatidylcholine and cholesterol) that lowers alveolar surface tension and maintains barrier integrity (Rindlisbacher et al., 2018; Liang et al., 2024; Chung et al., 2019; Whitsett et al., 2015; Ikegami et al., 1985).In pulmonary fibrosis, however, AEC2 lipid homeostasis collapses: single-cell profiles of IPF lungs show broad downregulation of genes for fatty-acid synthesis, β-oxidation and cholesterol biosynthesis in AEC2s, yielding lipid-poor cells and surfactant insufficiency (Rindlisbacher et al., 2018; Liang et al., 2024; Chung et al., 2019).In recent years, studies have shown that the abnormal lipid characteristics present in the serum of IPF patients and mouse IPF models are mainly the release of damaged AEC2, which subsequently participates in the fibrotic process (Yang et al., 2024). Among them, the metabolism of glycerophospholipids and choline underwent significant changes. The study by Baker DL et al. (Baker et al., 2006) identified lysophosphatidic acid, (LysoPA) in the serum of patients with IPF. LysoPC is the precursor of LPA, which is a bioactive glycerophospholipid. LPA induces pulmonary, renal and liver fibrosis through epithelial cell death, vascular leakage and fibroblast migration and proliferation (Alsafadi et al., 2017; Sakai et al., 2017; Kaffe et al., 2017; Tager et al., 2008). It is worth noting that after lung injury, dipalmitoyl phosphatidylcholine (DPPC), as the main surfactant lipid component, is degraded into LysoPC through the phospholipase A2 activity of AEC2, further exacerbating the process of pulmonary fibrosis (Beers et al., 2017; Shi et al., 2024). This change in lipid secretion profile is closely related to the decline of lung function, among which the depletion of phosphatidylcholine (PC) is particularly prominent. The level of PC in bronchoalveolar lavage fluid is significantly decreased, and it shows a significant negative correlation with the decline of lung compliance. Meanwhile, the research by Shi X et al. found that AEC2 can take up cholesterol from extracellular low-density lipoprotein through the low-density lipoprotein receptor (LDLR) (Shi et al., 2022). Adipocytes can transport lipids to AEC2 cells through the parathyroid hormone-associated protein (PTHRP) signaling pathway, which is activated by tensile-sensitive AEC2 cells and guides the differentiation of mesenchymal and alveolar epithelial cells (Chao et al., 2015; Torday and Rehan, 2002). These lipids may contribute to the synthesis of AEC2 surfactant lipids. To sum up, all these results indicate that the surfactant phospholipids in PF decrease, thereby exacerbating the course of IPF.

Furthermore, with the development of transcriptome and single-cell sequencing, the research results on the role of AEC2 lipid metabolic homeostasis in the development of IPF have been reported at both the cellular and organ levels. For example, Rindlisbacher et al. (2018) identified 500 downregulated genes involved in lipid metabolism, cholesterol handling, and steroid metabolism in AEC2 cells from PF patients by metabolomics analysis. Similarly, Liang et al. (2024) observed dysregulated expression of lipid metabolism genes in AEC2 cells from homeostatic, aged, and young mice following lung injury, as well as in PF patients, using scRNA-seq analysis. In particular, genes related to fatty acid synthesis (e.g., CHKA, SCD, FASN, etc.) and fatty acid β-oxidation (β-oxidation, a mitochondrial process that breaks down fatty acids to generate energy; e.g., ACAT1, ACSL) were significantly downregulated in AEC2 cells from IPF patients (Chung et al., 2019) (Figure 2).

Notably, the regulation of lipid homeostasis in AECs also closely linked to organelle integrity (Gunasekara et al., 2005; Mesmin, 2016). Studies have reported that endoplasmic reticulum (ER) stress is significantly increased in human and mouse AEC2 cells suffering from pulmonary fibrosis. Currently, a recognized adaptive response to ER stress is the induction of lipid synthesis by affected cells. For example, a negative correlation between the expression of lipid synthase and the expression of ER stress markers was observed in AEC2 cells from a mouse PF model (Romero et al., 2018a). Specifically, under PF conditions, increased ER stress in AEC2 resulted in impaired lipid synthesis, in particular a reduction in unsaturated fatty acid synthesis mediated by stearoyl coenzyme A desaturase 1 (SCD1) Reduced SCD1 activity not only impeded resolution of endoplasmic reticulum stress, but also exacerbated cellular dysfunction, thereby triggering a fibrotic response (Romero et al., 2018a).

In addition, mitochondrial dysregulation critically impacts lipid metabolism in PF. Mitochondrial dynamics—a process regulated by fission and fusion events—govern cellular energy homeostasis and functional adaptation (Toyama et al., 2016; Chen et al., 2003). Key mediators include the outer membrane GTPases MFN1 and MFN2, which coordinate mitochondrial fusion and directly regulate phospholipid/cholesterol synthesis in AEC2 (Shi et al., 2022; Chen et al., 2003). Disruption of this balance impairs surfactant lipid production, compromising epithelial barrier integrity and accelerating PF progression (Shi et al., 2022). Concurrently, diminished expression of CYB5R3 (a redox enzyme modulating NAD⁺/NADH equilibrium) in PF-associated AEC2 exacerbates mitochondrial dysfunction and aberrantly activates TGF-β1 signaling. This dual role positions CYB5R3 upregulation as a potential therapeutic strategy to restore epithelial stem cell function and mitigate metabolic derangements in PF (Rahaman et al., 2017; Hall et al., 2011; Bueno et al., 2023).

Recently, studies have found that autophagy-mediated metabolic reprogramming counteracts the fibrotic development process by regulating lipid fluxes during injury (Rahaman et al., 2017; Hall et al., 2011; Bueno et al., 2023; Galluzzi et al., 2017; Levine and Kroemer, 2019). In lung injury models, active autophagy in AEC2s shifts metabolism away from lipid storage toward energy production: autophagy downregulates fatty acid and triglyceride biosynthesis while upregulating glycolysis and β-oxidation to meet bioenergetic needs for repair (Araya et al., 2013). This “lipophagic” reprogramming helps clear toxic lipid intermediates and provides substrates for new membrane synthesis, thereby promoting AEC2 proliferation, surfactant regeneration, and barrier repair (Araya et al., 2013; Margaritopoulos et al., 2013). In contrast, impaired autophagy leads to accumulation of lipid byproducts and oxidative stress, which impairs regeneration and amplifies TGF-β1 signaling (Margaritopoulos et al., 2013; Li X. et al., 2020; Miller and Freeze, 2003; Hamanaka and Mutlu, 2021). Thus, ER stress, mitochondrial injury, and autophagy converge on AEC2 lipid metabolism: balanced regulation of lipid synthesis, desaturation, and degradation is essential for surfactant homeostasis and for restraining TGF-β1-driven fibrotic remodeling. (Figure 3).

Carbohydrate metabolism, a cornerstone of cellular energy supply and homeostasis, is profoundly altered in PF. Under physiological conditions, lung tissues exhibit a unique metabolic preference: approximately 40% of glucose is converted to lactate via glycolysis despite adequate oxygen availability—a phenomenon reminiscent of the “Warburg effect” observed in cancer (Korfei et al., 2008; Lee et al., 2004; Hui et al., 2017; Bassett and Fisher, 1976). In PF, this metabolic signature becomes pathological, with lactate levels in fibrotic lungs tripling compared to healthy tissues, driven by both overproduction and impaired clearance (Kottmann et al., 2012; Burman et al., 2018). AEC2 emerge as central players in this dysregulation. While healthy AEC2 utilize lactate for mitochondrial ATP synthesis (Lee et al., 2004), their PF counterparts undergo metabolic reprogramming characterized by defective oxidative phosphorylation and a shift toward glycolytic dominance. This shift is mediated by isoform-specific upregulation of lactate dehydrogenase (LDH): PF-associated AEC2 predominantly express LDH4/LDH5 isoforms that favor pyruvate-to-lactate conversion, contrasting with the LDH2/LDH3 dominance in non-fibrotic cells (Kottmann et al., 2012). The resultant lactate accumulation exerts multifaceted pro-fibrotic effects. It enhances TGF-β-induced myofibroblast differentiation through pH-dependent mechanisms (Newton et al., 2021), disrupts NAD⁺/NADH redox balance to accelerate cellular senescence (Li et al., 2019; Valdivieso et al., 2019; Massip-Copiz et al., 2021; Cui et al., 2022), and activates ER stress via the ATF4-Chop axis, triggering AEC2 apoptosis (Sun et al., 2024). Notably, therapeutic interventions targeting LDHA—a key glycolytic enzyme—reverse lactate-driven acidification and restore oxidative metabolism in PF models, mirroring findings in cystic fibrosis where CFTR mutations similarly elevate lactate through mitochondrial dysfunction (Newton et al., 2021; Valdivieso et al., 2019; Massip-Copiz et al., 2021). Collectively, these insights reposition lactate not merely as a metabolic byproduct, but as a pivotal mediator bridging glycolytic dysregulation to fibrotic tissue remodeling.

Energy metabolism dysregulation is a hallmark of PF, critically influencing disease progression. AEC2 responsible for surfactant production, exhibit profound mitochondrial dysfunction in PF, characterized by structural abnormalities (e.g., swelling), impaired mitophagy, and diminished biogenesis (Yan et al., 2023). These defects disrupt oxidative phosphorylation, reducing ATP synthesis while amplifying mitochondrial ROS (mtROS) generation—a toxic byproduct that perpetuates mitochondrial DNA damage and lipid peroxidation, thereby exacerbating both energetic crisis and fibrotic remodeling (Larson-Casey et al., 2020; Kim et al., 2016).

Central to mitochondrial quality control is the PINK1/Parkin-mediated mitophagy pathway. In PF, attenuated PTEN expression in lung epithelia sustains AKT activation and TGF-β signaling, further compromising epithelial integrity (Bueno et al., 2015). Concurrently, IL-17A exacerbates PF susceptibility by suppressing PINK1/Parkin activity, which disrupts mitophagy and amplifies apoptosis through dysregulated TGF-β, STAT3, and NF-κB pathways (Bueno et al., 2015). Beyond apoptosis regulation, autophagy sustains AEC2 proliferative capacity post-injury. Enhanced autophagy upregulates glycolytic enzymes (e.g., PGAM, ENO1, ALDOA) and glucose-6-phosphate dehydrogenase (G6PDX), boosting NADPH production to counteract oxidative stress while fueling alveolar repair (Li X. et al., 2020). This metabolic adaptation ensures redox homeostasis and maintains AEC2 regenerative potential. (Figure 4).

Glucose metabolism further modulates PF progression through key regulators. GLUT1 deficiency during lung injury impairs AEC2 proliferation despite compensatory upregulation of glycolysis and the pentose phosphate pathway (Newton et al., 2021). Similarly, diminished SIRT3 activity-a mitochondrial deacetylase vital for mtDNA integrity-promotes mitochondrial dysfunction and AEC apoptosis, highlighting the interplay between acetylation states and metabolic resilience (Xiao et al., 2022; Li J. et al., 2020; Bueno et al., 2018a). Collectively, these findings underscore that restoring AEC2 energy metabolism homeostasis represents a pivotal therapeutic avenue to mitigate fibrotic progression.

Glutamine plays a pivotal role in antioxidant defense through multiple mechanisms, including the production of NADPH, which regulates the synthesis of ROS detoxification enzymes, and serves as a core component of the cellular antioxidant glutathione. Studies have demonstrated that significant metabolic changes occur during glucose metabolism, necessitating cells to rely on alternative metabolic fuels like glutamine to support mitochondrial respiration and metabolite production, thereby inhibiting the progression of PF. Glutamine, an essential metabolic substrate, exhibits significantly elevated requirements in various pathological states (Vigeland et al., 2019; Wise and Thompson, 2010). Notably, the expression of key enzymes involved in glutamine metabolism (e.g., GLS1, GOT2, OGDH, SUCLG) is downregulated in AEC2 from PF patients and in bleomycin-induced mouse models of pulmonary fibrosis. This downregulation leads to inhibited glutamine metabolism and, consequently, impairs the proliferation and differentiation of AEC2 cells (Wang et al., 2022). Additionally, Shaghaghi et al. (Shaghaghi et al., 2021) found that glutamine supplementation reduces the cytotoxicity of bleomycin on AEC2 cells by restoring mitochondrial respiration in alveolar epithelial cells. Further investigations revealed that glutamine addition increases intracellular metabolite levels, including various tricarboxylic acid (TCA) cycle intermediates and the glycolytic intermediate lactate, and is associated with reduced DNA damage and cell death induced by bleomycin. These findings provide new insights into the role of amino acid metabolism in pulmonary fibrosis (Pullamsetti et al., 2011) (Figure 5).

Abnormalities in amino acid metabolism are particularly critical in the context of PF, especially the pathways involved in nitric oxide (NO) production. Asymmetric dimethylarginine (ADMA) is a by-product of arginine metabolism and acts as an inhibitor of endogenous NO synthase, which regulates the production of NO. Clinical data analysis shows that patients with IPF report higher levels of alveolar nitric oxide, which are closely related to the severity of the disease (Zhao et al., 2017; Masri, 2010). Pullamsetti et al. (2011) discovered that dimethylarginine dimethylaminohydrolase (DDAH) activity is increased in lung AEC2 cells of bleomycin-induced fibrotic mice and IPF patients due to an increase in TGF-β1 and IL-6. In AEC2 cells cultured from bleomycin-induced fibrotic mouse lung, inhibition of DDAH suppresses cell proliferation and induces apoptosis in an ADMA-dependent manner; it also reduces collagen production by fibroblasts in an ADMA-independent but transforming growth factor/SMAD-dependent manner (Pullamsetti et al., 2011; Masri, 2010).

Recent studies suggest that amino acid metabolism may offer a rapid and non-invasive way to better characterize IPF and simplify the diagnostic process. Gaugg et al. (2019) reported increased levels of proline, a key component of collagen, in the lung tissues of patients with IPF compared to healthy controls, which was attributed to an increased production of proline via the ornithine aminotransferase (OAT) pathway. Previous research has shown elevated lung levels of 4-hydroxyproline, as well as polyamine putrescine and spermidine, in IPF patients, supporting the notion that ornithine metabolism is dysregulated in PF (Zhao et al., 2017). In addition, Gaugg et al. (2019) further verified a significant increase in collagen-related amino acids (e.g., proline and 4-hydroxyproline) in IPF patients, suggesting that collagen metabolism and elevated extracellular matrix turnover are key factors in PF progression. By using real-time breath analysis technology (SESI-MS), this study successfully detected a variety of amino acids in the breath of PF patients, including proline, alanine, and lysine. This noninvasive assay is simpler and more clinically useful compared to traditional lung biopsies, showing potential as a diagnostic tool for PF. Notably, higher levels of certain amino acids, such as branched-chain amino acids (valine, leucine, and isoleucine), were associated with less severe disease damage, higher diffusion capacity of the lungs for carbon monoxide (DLco%), and lower composite physiological index (CPI). In addition to serving as key substrates for energy metabolism and protein synthesis, these amino acids regulate growth and energy metabolism by activating the mTOR pathway (Karna et al., 2020; Romero et al., 2016; Platé et al., 2020). mTOR is over-activated in fibroblasts and epithelial cells in the PF, making the relationship between their elevated circulating levels and mTOR activity in the lungs a subject worthy of further exploration.

In summary, the function of AEC2 cells is precisely regulated by multiple organelles and proteins to maintain normal amino acid metabolism. In the context of PF, disruption of these regulatory mechanisms may lead to abnormal metabolism, which in turn promotes the process of pulmonary fibrosis. Future studies need to further delve into the specific mechanisms of the role of these metabolic processes in pulmonary fibrosis, to provide new ideas and approaches for the treatment of the disease.

Lipid metabolism plays a crucial role in the function of AEC2 cells and the development of pulmonary fibrosis. Studies have shown that lipid metabolism not only affects energy metabolism and membrane stability in AEC2 cells but also is directly and closely related to the progression of the fibrotic process. Among them, acetyl coenzyme A synthase short-chain family member 3 (ACSS3) regulates ECM deposition by reducing fatty acid oxidation and enhancing anaerobic glycolysis through carnitine palmitoyltransferase type I alpha (CPT1A) deficiency. Therefore, ACSS3 is considered a potential therapeutic target for pulmonary fibrosis (Wang et al., 2024).

Lipid elongation and desaturation, mediated by enzymes like Elovl6 and stea-royl-coenzyme A desaturase (SCD), are critical for fatty acid biosynthesis. Elovl6 defi-ciency alters fatty acid composition in AEC2s, increasing palmitate (C16:0) and reduc-ing oleic acid (C18:1n-9) and linoleic acid (C18:2n-6), leading to metabolic disturb-ances that promote apoptosis, ROS production, and TGF-β1 signaling (Chen et al., 2023; Green et al., 2010; Moon et al., 2001; Matsuzaka et al., 2012). Inhibition of lipid biosynthesis through targeted deletion of fatty acid synthase (FASN) or SCD1 ex-acerbates mitochondrial dysfunction, ER stress, and fibrosis, while overexpression of FASN or activation of liver X receptor (LXR) agonists attenuates fibrotic progression (Chung et al., 2019; Shin et al., 2023). These findings underscore the importance of lipid metabolism in maintaining AEC2 function and limiting.

Lipid synthesis is regulated by various factors, and beyond lipid synthases, lipid metabolism-related proteins play an important role in this process. Apolipoprotein A1 (APOA1), a major protein component of high-density lipoprotein (HDL), belongs to the serum apolipoproteins (Kim et al., 2010). Lee et al. (2013) found that APOA1, in AEC2 cells with PF, may inhibit the production of TGF-β1 and reduce the number of apoptotic cells by increasing the level of the lipid mediator LXA4, which may reduce early and established lung inflammation and fibrosis. Furthermore, Gordon et al. (2016) revealed that APOA1, in AEC cells in lung tissue, prevents lipid overload and removes excess lipids from the cells. This further emphasizes the important role of APOA1 in protecting against lung injury and fibrosis. With a deeper understanding of the role of lipid metabolism in PF, more studies are revealing the potential to intervene in the fibrotic process by modulating lipid metabolism. The finding that metformin, an AMPKα activator and lipid synthesis inhibitor, has been shown to be effective in reversing the process of established pulmonary fibrosis in mice further emphasizes the critical role of lipid metabolism in IPF (Zelcer and Tontonoz, 2006). In addition, recent studies have shown that the FDA-approved lipid-lowering drugs fenofibrate and ciprofibrate significantly attenuated the extent of pulmonary fibrosis and reduced collagen production in fibroblasts and myofibroblast differentiation in mice (Samah et al., 2012), providing new evidence for the use of lipid metabolism modifiers in the treatment of pulmonary fibrosis. At the same time, studies have begun to focus on the role of lipid receptors and lipid delivery systems in the treatment of pulmonary fibrosis. For example, preclinical studies have shown that blocking certain lipid receptors (e.g., GPR84, LPA1, or CysLT1), as well as activating GPR40, may have an anti pulmonary fibrosis effect. In addition, Gwinn et al. (2011) found that local delivery of liposomes consisting of L-α-phosphatidylcholine and cholesterol effectively alleviated bleomycin-induced lung injury in mice. Similarly, Kornilova et al. (2001) demonstrated that phosphatidylcholine liposomes promoted wound healing in a guinea pig surgical lung injury model. These studies further emphasize the important role of lipid metabolism regulation in the treatment of pulmonary fibrosis and provide new directions for future therapeutic strategies.

Emerging evidence indicates that metabolic derangements and ER stress form a feed-forward loop that aggravates AEC2 dysfunction in pulmonary fibrosis. High-fat diets enriched in palmitic acid worsen bleomycin-induced fibrosis by driving lipid overload, AEC2 cell death, and unresolved ER stress, thereby potentiating TGF-β signaling and matrix deposition (Kornilova et al., 2001; Chu et al., 2019). Conversely, restoring balanced lipid metabolism in AEC2s can mitigate ER stress and fibrosis. For example, enhancement of SCD1 activity or supplementation with monounsaturated fatty acids not only replenishes surfactant phospholipids but also alleviates ER stress markers (BiP, CHOP) and reduces collagen accumulation in fibrotic lungs (Summer and Mora, 2019). Similarly, administration of epoxyeicosatrienoic acids (EETs) via the CYP2J2 pathway improves redox homeostasis in AEC2s, promotes Nrf2-dependent antioxidant responses, and indirectly stabilizes ER function by preserving phospholipid bilayer integrity (Zhang et al., 2023).

Therapeutically, combining lipid-centric strategies with ER stress modulators yields synergistic benefits. Citrus aurantium alkaline extract (CAE), for instance, activates ATF3/PINK1-mediated mitophagy, resets fatty-acid β-oxidation, and lowers ER stress, collectively enhancing AEC2 survival and reducing fibrotic remodeling. Likewise, overexpression of Sestrin2 in AEC2s suppresses ROS and pro-inflammatory cytokine release (TNF-α, IL-6, IL-1β), prevents lipid peroxidation, and curbs ER-stress–induced ferroptosis, thereby preserving surfactant synthesis and barrier integrity (Zhang et al., 2023; Wang et al., 2021). These findings underscore that targeted restoration of lipid metabolic homeostasis—in particular, promoting desaturation (via SCD1), supporting physiologic phospholipid pools, and enhancing lipophagy—can potently attenuate ER stress (Zhang et al., 2023; Wang et al., 2021; Dong et al., 2023) (Table 1).

Emerging studies indicate that metabolic reprogramming in AEC2 contributes to lactate accumulation in pulmonary fibrosis, which exacerbates fibrotic progression by activating TGF-β/mTOR signaling and suppressing anti-fibrotic miRNAs such as the miR200 family (Acharya et al., 2019; Abedini et al., 2011; Gilbert et al., 2015; Song et al., 2022; Middleton et al., 2018; Zhang et al., 2016; Di Gregorio et al., 2020). LDHA, a key glycolytic enzyme upregulated in IPF-AEC2, has been identified as a critical driver of this process. Preclinical evidence demonstrates that LDHA inhibition via RNAi restores oxidative phosphorylation balance and normalizes metabolic profiles in fibrotic AEC2, suggesting therapeutic potential (Newton et al., 2021). This has spurred interest in repurposing LDHA-targeted small-molecule inhibitors (currently under investigation in cancer and neurodegenerative diseases (Acharya et al., 2019; Abedini et al., 2011; Gilbert et al., 2015)) for IPF treatment. However, systemic LDHA inhibition carries significant risks: as a central glycolytic enzyme, its broad suppression may disrupt lactate-dependent physiological functions in high-demand organs (e.g., heart and skeletal muscle) and trigger compensatory mechanisms such as ROS-JNK/p38 MAPK pathway activation, potentially worsening fibrosis. These risks mirror challenges observed with other metabolic modulators—for instance, JAK inhibitors (e.g., Ruxolitinib) ameliorate fibrosis but risk immunosuppression (Song et al., 2022), while epigenetic agents like Rhein alleviate renal fibrosis yet may perturb DNA methylation (Middleton et al., 2018; Zhang et al., 2016). Collectively, these findings highlight the need for tissue-specific delivery strategies and comprehensive risk-benefit assessments when targeting LDHA in IPF (Newton et al., 2021; Song et al., 2022; Middleton et al., 2018; Zhang et al., 2016).

Mitochondrial health is essential for AEC2s to fully oxidize glycolytic pyruvate and meet high ATP demands during repair. In IPF, suppressed PINK1 expression—due in part to ATF3 overexpression—leads to accumulation of damaged mitochondria, a shift toward anaerobic glycolysis, and lactate buildup that fuels fibroblast activation and matrix deposition (Xiao et al., 2022; Moimas et al., 2019; Lawrence and Nho, 2018; Judge et al., 2018). IL-17A further disrupts mitophagy and exacerbates ER stress, reinforcing the glycolytic bias of AEC2s and reducing their regenerative capacity (Bueno et al., 2015; Hartman et al., 2004; Bueno et al., 2018b). Restoring PINK1 via ATF3 knockdown or IL-17A neutralization re-establishes mitophagy, increases mitochondrial respiration, and shifts carbon flux back toward oxidative phosphorylation. This metabolic rebalancing lowers lactate levels, diminishes TGF-β1 activation, and improves AEC2 survival and barrier function, demonstrating that targeting the PINK1/ATF3/IL-17A axis is a viable approach to correct carbohydrate metabolism in fibrotic lungs (Wang et al., 2017; Mi et al., 2011).

Beyond mitochondrial rescue, direct modulation of glycolysis and NAD⁺/NADH balance can further restore AEC2 energy homeostasis. Inhibition of LDHA reduces lactate production, preventing extracellular acidification that drives profibrotic signaling, while supplementation with NAD⁺ precursors (e.g., nicotinamide riboside) enhances sirtuin-mediated mitochondrial biogenesis and promotes pyruvate entry into the TCA cycle (Cui et al., 2022). Targeting glucose uptake via conditional GLUT1 deletion in AEC2s has shown that fine-tuning glucose influx can prevent excessive glycolytic flux and AEC2 apoptosis under stress (Bueno et al., 2015). Moreover, ER chaperones that relieve UPR-induced translational arrest (e.g., 4-phenylbutyrate) synergize with glycolytic inhibitors to reduce ATF4/CHOP-mediated cell death and preserve ATP production through balanced glycolysis–OXPHOS coupling (Yan et al., 2023; Larson-Casey et al., 2020; Kim et al., 2016). (Table 1)