While the systemic inflammatory response induced by bacterial sepsis is a well-recognized contributor to AEC injury, emerging evidence suggests that AECs themselves can actively participate in the inflammatory cascade. Under certain pathological conditions, AECs are capable of producing pro-inflammatory cytokines and chemokines, thereby amplifying systemic inflammation and contributing to multi-organ damage in conditions such as sepsis, ALI, and ischemia-reperfusion injury (66). Furthermore, AECs engage in crosstalk with immune cells, modulating both local pulmonary inflammation and broader immune responses. These interactions can disrupt alveolar structure and impair respiratory function, further exacerbating disease progression (67).

NF-κB plays a pivotal role in various physiological and pathological processes, including immune and inflammatory responses, cell survival, proliferation, and metabolism. It is critical in cellular responses to external stimuli, such as cytokines, stress, and antigens (85). In the context of bacterial Sepsis-Associated ALI, endotoxins induce AEC apoptosis and inflammatory responses through the regulation of the NF-κB/p65 signaling pathway (86), thereby inhibiting AEC apoptosis mediated by cytochrome C and caspase-3. Targeting NF-κB protein levels (87, 88) or inhibiting its activity (89) can reduce AEC inflammatory injury and alleviate bacterial Sepsis-Associated ALI. Further studies have shown that during septic inflammatory storms, NF-κB activation enhances the release of inflammatory mediators - including TNF-α, IL-1β, and Monocyte Chemoattractant Protein-1 (MCP-1) - while simultaneously promoting NET formation through NLRP3 inflammasome activation, thereby exacerbating pulmonary inflammation (90). Notably, NETs also facilitate m6A methylation modification, leading to the degradation of GPX4 mRNA via the Toll-like Receptor 9 (TLR9)/Myeloid Differentiation Primary Response 88 (MyD88)/NF-κB/methyltransferase-like 3 (METTL3) signaling pathway, thus reducing GPX4 protein expression and promoting AEC ferroptosis (72, 91). Reticulocalbin 3 (Rcn3) regulates the NF-κB/NLRP3/inflammasome axis, thereby protecting AECs and alleviating bacterial Sepsis-Associated ALI (92). Endotoxin-stimulated AEC exosomes secrete TNC, which binds to Toll-like Receptor 4 (TLR4) receptors and activates the P38/extracellular signal-regulated kinase (ERK)/NF-κB pathway, driving M1 macrophage polarization and inducing macrophage pyroptosis, thereby further intensifying inflammatory responses in bacterial Sepsis-Associated ALI (78). Additionally, PGN from Staphylococcus aureus cell walls can induce IL-8 expression through CD14 enhancement, ultimately activating NF-κB in AECs and promoting the development of bacterial Sepsis-Associated ALI (73). Cell and animal experiments have also confirmed that miR-92a-3p in AEC exosomes targets Phosphatase and Tensin Homolog (PTEN), activating the NF-κB/p65 signaling pathway in macrophages via the Phosphoinositide 3-Kinase (PI3K)/Protein Kinase B (Akt) pathway, thereby promoting the release of inflammatory cytokines and inducing pulmonary inflammation (79). Anemonin can inactivate NF-κB, thereby inhibiting lipopolysaccharide-induced AEC inflammation and oxidative stress, and alleviating bacterial Sepsis-Associated ALI (93). These findings underscore the central role of NF-κB in orchestrating complex inflammatory networks through various cellular and molecular mechanisms in the pathogenesis of bacterial Sepsis-Associated ALI.

Phosphorylation is the most prevalent post-translational modification, playing a critical role in regulating protein function and cellular functions. Dysregulated phosphorylation contributes to various diseases by affecting cell signaling, transmembrane protein synthesis, and key biological pathways, including apoptosis and autophagy (94). Phosphorylation is closely linked to the regulation of NF-κB in bacterial Sepsis-Associated ALI. Studies have shown that endotoxins activate ERK1/2 and p38/MAPK phosphorylation, leading to the translocation of cytoplasmic NF-κB to the nucleus and the activation of NF-κB activity. This may increase the expression of immune response-related TLR2 and modulate the expression of surfactant protein A (SP-A), which exacerbates bacterial Sepsis-Associated ALI (95). In contrast, activation of PI3K-Akt phosphorylation negatively regulates NF-κB phosphorylation, thereby inhibiting AEC apoptosis, alleviating bacterial Sepsis-Associated ALI, and reducing mortality in experimental models (96, 97). Additionally, modulation of P65 phosphorylation, a key factor in the NF-κB signaling pathway, has been shown to mitigate bacterial sepsis-induced AEC injury and reduce pulmonary inflammation in septic mice (98). Moreover, endotoxins promote c-Jun N-terminal Kinase (JNK) signaling pathway phosphorylation in a time-dependent manner, leading to AEC apoptosis (99).

In summary, modulation of the NF-κB signaling pathway and its phosphorylation is one of the key targets for regulating AEC injury and repair in bacterial Sepsis-Associated ALI. Recent treatments targeting the NF-κB signaling pathway to alleviate ALI have also proven effective in the treatment of Coronavirus Disease 2019 (COVID-19) (100). However, due to the significant Heterogeneity of ALI caused by different factors, the effectiveness of these drugs in ALI caused by various factors still requires further research. Additionally, activation of the canonical NF-κB/p65 pathway in AECs regulates the expression of coagulation and fibrinolysis-related proteins, such as tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) (101). However, the precise molecular mechanisms underlying these effects require further investigation.

NRF2 is the master regulator of the antioxidant response element (ARE) pathway. By binding to AREs in target gene promoters, NRF2 coordinates the expression of various cytoprotective enzymes and proteins, playing a critical role in redox homeostasis, oxidative stress defense, and cellular stress responses (102). In bacterial Sepsis-Associated ALI, endotoxins have been shown to suppress the NRF2/heme oxygenase-1 (HO-1) signaling pathway, exacerbating AEC inflammation, oxidative stress, and ferroptosis. Conversely, several agents, including AU-rich element ARE-binding factor 1 (AUF1) (103), mesenchymal stem cell (MSC)-derived exosomes (88), ferulic acid (104), and sufentanil (105), Ciprofol (106), and Anemonin (93) activate NRF2, thereby inhibiting AEC inflammation, oxidative stress, and cellular ferroptosis and apoptosis, ultimately alleviating bacterial Sepsis-Associated ALI progression. NRF2 also promotes the production of IL-17D in AECs, exerting a protective role in bacterial Sepsis-Associated ALI (107). Furthermore, NRF2 is involved in METTL4-mediated m6A methylation modification, thereby regulating mitochondrial homeostasis and cellular ferroptosis in bacterial Sepsis-Associated AECs (9). MSC-derived exosomes activate the NRF2 pathway, regulating processes like mitochondrial biogenesis and fission, maintaining mitochondrial function homeostasis, reducing LPS-induced AEC apoptosis, and alleviating bacterial Sepsis-Associated ALI in mice (108). Lysophosphatidylcholine (LPC) 14:0, by activating the NRF2/HO-1 signaling pathway, can also inhibit LPS-induced degradation of tight junction proteins, protecting AEC barrier function (109). These findings suggest that NRF2 plays a key role in the regulation of inflammation, oxidative stress, mitochondrial homeostasis, and barrier function maintenance in sepsis-related AEC injury. Targeting NRF2 could impact multiple aspects of bacterial sepsis-associated AEC damage, making it a potential therapeutic target for bacterial Sepsis-Associated ALI.

NLRP3 inflammasome is a multiprotein complex that plays a pivotal role in regulating inflammatory responses and processes such as pyroptosis through its signaling, regulatory, and effector functions (49, 110). In bacterial sepsis, endotoxins activate the NLRP3 inflammasome in both macrophages (76, 111) and AECs (14, 112), promoting AEC apoptosis, pyroptosis, and the release of inflammatory cytokines. This activation amplify inflammatory cell infiltration and exacerbate lung injury. This activation triggers programmed cell death and the release of pro-inflammatory cytokines, which in turn amplify inflammatory cell infiltration and exacerbate lung injury. Therapeutic strategies aimed at inhibiting NLRP3 activation, such as promoting NLRP3 degradation (51) or using anti-inflammatory compounds like Phillyrin (a natural lignan derived from Forsythia) (50) and Calycosin (an extract from Astragalus membranaceus) (72), have shown efficacy in reducing inflammatory cytokine production and the release of NETs. These interventions help alleviate AEC pyroptosis, apoptosis, and inflammatory responses, thereby mitigating the progression of bacterial Sepsis-Associated ALI.

In summary, in addition to regulating inflammatory responses, NLRP3 also plays a key role in apoptosis, pyroptosis, and other forms of programmed cell death in bacterial Sepsis-Associated AEC injury. Its mechanism may be related to the formation of the PANoptosome, which drives cell pyroptosis, apoptosis, PANoptosis, and necroptosis (113, 114). However, the specific molecular mechanisms and how NLRP3 regulates these processes in bacterial Sepsis-Associated ALI still require further investigation.

High-mobility group (HMG) proteins are a family of evolutionarily conserved, non-histone nuclear proteins characterized by their high electrophoretic mobility. Among them, high-mobility group box (HMGB) proteins are the most abundant, comprising four isoforms: HMGB1, HMGB2, HMGB3, and HMGB4 (115). In bacterial Sepsis-Associated ALI, LPS promotes AEC inflammation and apoptosis via the HMGB1/receptor for advanced glycation end products (RAGE) pathway (116). Pharmacological agents with anti-inflammatory properties, such as calycosin (72) and propofol (89), have been shown to mitigate sepsis-induced AEC injury by inhibiting HMGB1-mediated activation of downstream inflammasomes and signaling pathways, thereby alleviating bacterial Sepsis-Associated ALI. Additionally, increased serum HMGB3 mRNA levels in bacterial Sepsis-Associated ALI patients, along with the involvement of the miR-424-5p/HMGB3 axis in sepsis-induced AEC inflammation and apoptosis (117), suggest that targeting HMGB proteins may offer a novel therapeutic approach for managing AEC dysfunction in sepsis. Targeting HMGB proteins or their signaling pathways may provide new therapeutic strategies for the treatment of bacterial Sepsis-Associated ALI. However, a deeper understanding of the molecular mechanisms by which HMGB proteins regulate inflammation and apoptosis, as well as the clinical validation of potential drugs and biomarkers, is essential for developing effective treatments. As research progresses, it may become possible to design novel therapies specifically targeting HMGB1, HMGB3, and their associated pathways to alleviate the impact of bacterial Sepsis-Associated ALI.

TLR, an evolutionarily conserved family within the innate immune system, act as the first line of defense against microbial pathogens by recognizing pathogen-associated molecular patterns (PAMPs). Dysregulated TLR responses contribute to a range of inflammatory and immune disorders (118). During bacterial Sepsis-Associated ALI, NETs regulate AEC functionality and disease pathogenesis through TLR9 pathway activation, which subsequently modulates METTL3-dependent methylation patterns (91). Furthermore, endotoxin exposure upregulates TLR2 expression (95), initiating a downstream signaling cascade through MyD88, mitogen-activated protein kinase 4 (MEK4), JNK1, and AP-1. This signaling axis stimulates alveolar epithelial cells (AECs) to overproduce surfactant protein-A (SP-A), thereby exacerbating the pathogenesis of bacterial Sepsis-Associated ALI (119). Together, these findings highlight the significant role of TLR activation in influencing AEC function and surfactant protein production during bacterial Sepsis-Associated ALI. These insights suggest that targeted modulation of TLR expression could provide a promising therapeutic approach for managing bacterial Sepsis-Associated ALI (87). Further research could focus on developing drugs that target TLRs to intervene and alleviate sepsis-associated AEC injury.

The heterodimeric core complex consisting of methyltransferase-like 3 and 4 (METTL3/4) catalyzes N6-methyladenosine (m6A) methylation, a prevalent modification in mammalian messenger RNA (mRNA) and non-coding RNA. This modification plays a critical role in regulating mRNA stability, processing, and translation (120). In the context of bacterial sepsis, lactate and NETs upregulate METTL3 expression by activating p300 histone acetyltransferase-mediated enhancer modifications (H3K27ac and H3K18la) (3, 53). These changes promote m6A methylation of mRNAs such as Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4), HIF-1α, GPX4, and SIRT1, stabilizing ACSL4 and HIF-1α transcripts while enhancing degradation of GPX4 and SIRT1 mRNAs. This molecular regulation contributes to AEC ferroptosis and autophagic dysfunction in bacterial Sepsis-Associated ALI (121). Moreover, METTL4 exacerbates endotoxin-induced AEC mitochondrial dysfunction and ferroptosis by enhancing the interaction between YTH N6-Methyladenosine RNA Binding Protein 2 (YTHDF2) and NRF2, leading to increased m6A modification and degradation of NRF2 mRNA (9). DNA methyltransferase 1 (DNMT1) further amplifies inflammatory responses through the DNMT1/miR-130a/Zinc Finger E-Box Binding Homeobox 1 (ZEB1) axis, promoting the secretion of inflammatory factors from AECs (30). In summary, methyltransferase-mediated modifications critically regulate mRNA metabolism and contribute to sepsis-induced AEC injury and inflammation. Targeted modulation of methyltransferase activity may offer a promising therapeutic strategy to alleviate AEC dysfunction and mitigate the progression of bacterial Sepsis-Associated ALI (120, 122). Targeting methylation-modifying enzymes, such as METTL3, METTL4, and DNMT1, provides a promising therapeutic strategy to regulate gene expression, alleviate AEC dysfunction, and slow the progression of bacterial Sepsis-Associated ALI. However, the precise molecular mechanisms by which these modifications regulate cellular responses in sepsis remain to be explored, making this an essential area for future research.

MAPK family consists of a series of signaling molecules that transduce signals from the cell surface to the nucleus. MAPKs play a crucial role in various cellular processes, including proliferation, stress responses, inflammation, differentiation, transformation, apoptosis, and other signaling pathways. In mammals, the conventional MAPK family consists of four subfamilies: ERK, JNK, p38, and ERK5. The MAPK/ERK pathway is primarily involved in cell proliferation, differentiation, and the activation of various growth factor receptors. The MAPK/p38 pathway mainly mediates cellular responses related to inflammation and apoptosis, while the MAPK/JNK pathway participates in cellular stress responses such as radiation and osmotic stress (123).

In bacterial Sepsis-Associated ALI, the MAPK signaling pathway critically regulates NF-κB activation and phosphorylation, contributing to disease pathogenesis (for detailed mechanisms, refer to the section on NF-κB and Phosphorylation). Notably, studies have demonstrated that suppressing histone deacetylase 4 (HDAC4) expression attenuates LPS-induced alveolar epithelial cell (AEC) inflammation and oxidative stress by inhibiting the JNK/AP-1 signaling axis. This intervention improves mitochondrial function and reduces AEC apoptosis (124). Sea buckthorn has been shown to inhibit the LPS-induced upregulation of MAPK3 expression in AECs, suppress ferroptosis, and enhance cell vitality (54). Studies in sepsis patients with COVID-19 pneumonia have also found that Rapidly Accelerated Fibrosarcoma (RAF)/MEK/ERK pathway activation may be associated with immune system recovery, correlating with patient survival rates (125). In summary, the MAPK signaling pathway plays a significant role in regulating AEC inflammation and cell injury in bacterial Sepsis-Associated ALI. Modulating the MAPK signaling pathway offers a potential therapeutic approach to improve AEC damage in bacterial Sepsis-Associated ALI. However, the specific molecular mechanisms and potential drug candidates remain to be further explored through in-depth research.

Vascular leakage and alveolar edema are significant pathological changes in bacterial Sepsis-Associated ALI. In bacterial Sepsis-Associated ALI, endotoxins reduce the expression and increase the degradation of ion channels and water channel proteins in AECs, including ENaC, Na,K-ATPase AQP1, and AQP5, leading to decreased alveolar fluid clearance, increased pulmonary edema, and lung exudation, thus exacerbating bacterial Sepsis-Associated ALI (64, 65). Postmortem examinations of patients with diffuse alveolar damage have also shown an increased expression of AQP3, AQP5, and Na-K-ATPase, and a decreased expression of ENaC (126). Modulating the expression of water channel proteins, ENaC, and Na+,K+-ATPase can reduce pulmonary edema and lung tissue pathology by influencing alveolar fluid clearance, thus improving lung compliance, lung function, and survival rates in experimental animals (127, 128). Additionally, studies have found that water channel proteins such as AQP4 and AQPs are associated with inflammasome activation, while AQP3, AQP7, AQP9, and AQP10 enhance glycolysis during sepsis by promoting glycerol transport, supporting glucose uptake, and interacting with various metabolic signaling pathways, thereby regulating the immune cell energy supply and immune metabolism (129–131). In summary, ion channel-related proteins play a crucial role in regulating alveolar fluid balance, immune cell activation, and inflammatory responses in bacterial Sepsis-Associated ALI. However, the relationship and mechanisms by which these proteins modulate immune cell activation and inflammation, in connection to AEC damage in bacterial Sepsis-Associated ALI remain to be further explored.

Ubiquitination is a key post-translational modification regulated by the coordinated action of E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin ligases. This process facilitates the covalent attachment of ubiquitin to target proteins, influencing signaling pathways and the assembly or degradation of protein complexes (132). In bacterial Sepsis-Associated ALI, several ubiquitination-related enzymes have been implicated in AEC injury and inflammation. These include ubiquitin-specific peptidases (USP10, USP38) (71, 133), E3 ubiquitin ligases, including S-phase kinase-associated protein 2 (SKP2) and F-box/WD repeat-containing protein 7 (FBXW7) (51, 103), and the trimeric E3 ligase family member Ring finger protein 99 (98). These enzymes regulate the ubiquitination and deubiquitination of key proteins such as GPX4, NLRP3, and AUF1, with their modulation offering potential therapeutic benefits in mitigating AEC injury and bacterial Sepsis-Associated ALI progression. Additionally, erythropoietin (EPO) has been shown to inhibit endotoxin-induced ubiquitin-mediated degradation of ENaC and Na,K-ATPase in AEC II via the EPOR/JAK2/STAT3/SGK1/Nedd4-2 pathway. This intervention enhances alveolar fluid clearance, alleviates bacterial Sepsis-Associated ALI pathology, restores pulmonary function, and improves survival outcomes in experimental models (63). Collectively, these findings highlight the therapeutic potential of targeting ubiquitination pathways in bacterial Sepsis-Associated ALI, with beneficial effects observed in protein homeostasis regulation, AEC protection, inflammation reduction, and alveolar fluid balance restoration. The ubiquitination regulatory system plays a dual role in the pathogenesis of bacterial Sepsis-Associated ALI: it contributes to the amplification of harmful inflammation and apoptosis, while also exerting protective effects by regulating protein stability and function to promote alveolar repair and fluid clearance. Therefore, precise modulation of ubiquitination enzymes and their associated signaling pathways may offer novel strategies for the intervention and treatment of ALI.

Acetylation and deacetylation exhibit target diversity and are post-translational modifications closely linked to metabolism. They are highly sensitive to the concentrations of acetyl-CoA, acyl-CoA, and Nicotinamide Adenine Dinucleotide (NAD), playing critical roles in various cellular and physiological processes such as transcription, autophagy, mitosis, and differentiation (134). These modifications are involved in the pathogenesis of bacterial sepsis-induced organ dysfunction, contributing to progression of the disease (135). In sepsis-mediated AEC injury, histone deacetylases Histone Deacetylase 3 (HDAC3) (60) and SIRT1 (69, 121) play key roles in regulating AEC autophagy, oxidative stress, mitochondrial dysfunction, and inflammatory factor release, thereby influencing AEC viability. Notably, HDAC3 also suppresses the expression of intercellular junction proteins, compromising epithelial integrity, increasing permeability, and exacerbating bacterial Sepsis-Associated ALI progression (60). Conversely, SIRT3 exerts protective effects by inhibiting lipopolysaccharide-induced acetylation of OPA1 at K792 in alveolar macrophages (77) and promoting the deacetylation of Superoxide Dismutase 2 (SOD2) at K122/K68 in AECs (136). These mechanisms contribute to mitochondrial quality control, suppress macrophage polarization, and regulate AEC autophagy and fatty acid oxidation. Ultimately, SIRT3 activity reduces oxidative stress, mitigates cellular damage, and preserves barrier function, thereby alleviating bacterial Sepsis-Associated ALI. These findings underscore the importance of acetylation and deacetylation dynamics in bacterial sepsis, which modulate autophagy, oxidative stress, and mitochondrial dysfunction to influence AEC inflammatory responses, injury, and barrier integrity. Targeting this intricate post-translational regulatory network represents a promising therapeutic strategy for bacterial Sepsis-Associated ALI management.

Exosomes, small extracellular vesicles involved in intercellular communication, mediate the transfer of proteins, lipids, and nucleic acids, influencing immune responses, metabolic reprogramming, coagulopathy, and organ dysfunction in bacterial sepsis (137). Studies indicate that serum exosomes from sepsis patients induce oxidative stress, inflammation, and AECs injury via the Diacylglycerol Kinase (DGK)/Diacylglycerol (DAG)/Protein Kinase C (PKC)/NADPH Oxidase 4 (NOX4) pathway (25). Additionally, endotoxin-stimulated alveolar macrophages release exosomes that activate AEC inflammasomes, promoting inflammatory responses (76). In turn, AEC-derived exosomes amplify pulmonary inflammation by activating inflammatory signaling in macrophages, exacerbating mitochondrial damage, and inducing macrophage apoptosis—processes that may be mitigated by inhibiting AEC exosome release, a potential therapeutic approach for bacterial Sepsis-Associated ALI (78, 79). Furthermore, MSC cell-derived exosomes have shown protective effects by maintaining mitochondrial homeostasis, suppress lipopolysaccharide-induced inflammatory cytokine release in AECs through NRF2 and NF-κB-related signaling pathways, thereby alleviating bacterial Sepsis-Associated AEC apoptosis and promoting cell proliferation (88, 108). Collectively, these findings highlight the role of exosomes in bacterial Sepsis-Associated ALI pathogenesis and suggest their potential as both biomarkers of bacterial sepsis-induced AEC damage and therapeutic agents. Modulating endogenous exosome secretion or administering exogenous exosomes may represent a promising strategy for bacterial Sepsis-Associated ALI treatment ( Figure 3 ).

As discussed, bacterial sepsis-induced AEC injury is a crucial mechanism in the development of bacterial Sepsis-Associated ALI. Research has identified several therapeutic agents that alleviate AEC apoptosis and ferroptosis, thus exerting protective effects on the lungs and mitigating the severity of bacterial Sepsis-Associated ALI. For example, metformin (138), bovine alveolar surfactant (47), ulinastatin (143), simvastatin (86), pyrrole derivatives (87), ginsenoside Rg1 (97, 144), recombinant Klotho protein (48) and Ciprofol (106) have all demonstrated lung-protective effects. Traditional Chinese medicines, including sea buckthorn (54) and shikonin (55), inhibit AEC ferroptosis, while the human antimicrobial peptide LL-37 (49) and natural lignan phillyrin (PHI) derived from Forsythia suspensa (50) suppress AEC pyroptosis, thus reducing AEC injury and mitigating inflammatory responses in bacterial Sepsis-Associated ALI. Antioxidants such as N-acetylcysteine (NAC) (35), melatonin (136), and tea polyphenols (139) have shown efficacy in attenuating bacterial Sepsis-Associated ALI by reducing ROS and RNS production, thus alleviating oxidative stress and improving mitochondrial function. Additionally, the omega-3 fatty acid-derived lipid mediator resolvin E1 (RvE1) has demonstrated protective effects against inflammation-induced mitochondrial dysfunction in AECs during severe inflammatory states (140). Furthermore, small-molecule modulators targeting specific signaling pathways, including the α7 Nicotinic Acetylcholine Receptor (α7nAChR) agonist PNU-282987 (141), miR-155 inhibitor (69), Receptor-Interacting Protein Kinase 3 (RIPK3) inhibitor UH15-38 (15), Glycogen Synthase Kinase-3 Beta (GSK-3β) inhibitor Tideglusib (138), and glycolysis inhibitor 3PO (42), have shown promise in improving bacterial Sepsis-Associated ALI outcomes through the regulation of AEC activity. In summary, therapeutic strategies aimed at modulating AEC activity, oxidative stress responses, and mitochondrial function offer promising approaches for mitigating AEC injury and promoting cellular repair and regeneration in bacterial Sepsis-Associated ALI. Clinical studies have also shown that the combination of ginsenoside Rg1 and ulinastatin in treating sepsis-associated ALI can significantly improve hemodynamic and pulmonary circulation parameters, such as cardiac index, intrathoracic blood volume index, and central venous pressure (142). However, the lack of clinical trial validation presents significant translational challenges, including the need for optimal drug selection and rigorous preclinical evaluation to ensure clinical safety and efficacy. This gap underscores the need for extensive future research to bridge the divide between preclinical findings and clinical application. In summary, therapeutic strategies aimed at modulating AEC activity, oxidative stress, and mitochondrial function to alleviate AEC injury and promote cellular repair and regeneration represent a promising approach to treating bacterial Sepsis-Associated ALI. However, most of these drugs currently lack relevant clinical randomized controlled trials. The selection of optimal drugs, drug formulations, and treatment plans, as well as the evaluation of their clinical safety and efficacy, still require further research. There is still a long way to go before these approaches can be applied in clinical settings.

Impairment of AEC barrier function is also a significant cause of pulmonary inflammatory exudation in bacterial sepsis. In bacterial Sepsis-Associated ALI, inhibiting the degradation of tight junction proteins or using ferulic acid (FA) to improve the expression of tight junction proteins in bacterial sepsis-associated AECs can improve AEC barrier dysfunction and alleviate lung tissue damage (104, 109). Similarly, antimicrobial therapies and microbiota modulation can regulate junctional proteins, improving bacterial Sepsis-Associated ALI and increasing survival rates in experimental models (59). Additionally, pharmacological agents such as dexamethasone (62), erythropoietin (EPO) (63), and the anti-inflammatory formulation Yan Tiao Decoction (65) have been reported to regulate ion channels in AECs, including ENaC, Na,K-ATPase, NKAα1, NKAβ1, AQP1, and AQP5. These agents promote alveolar fluid clearance, thereby mitigating the pathological effects of bacterial Sepsis-Associated ALI. These findings suggest that modulating the expression of both AEC junctional proteins and ion channels through pharmacological interventions to restore alveolar barrier function and promote fluid resolution may be one of the potential therapeutic strategies for bacterial Sepsis-Associated ALI. However, key issues such as drug selection and intervention timing still require further in-depth research (Figure 3).

Bacterial sepsis-induced dysregulation of inflammatory cytokine release from AECs and their interactions with immune cells play a critical role in the pathogenesis of pulmonary inflammation. Recent studies have highlighted the potential of anti-inflammatory agents, including methylprednisolone (71, 145), dexamethasone (62), propofol (89), sufentanil (105), calycosin (72), Klotho (48), Ciprofol (106), and Anemonin (93) to attenuate septic lung inflammation and injury. These agents act by suppressing inflammasome activation and downstream signaling pathways in AECs, thereby reducing pro-inflammatory cytokine production. Additionally, MSC-derived exosomes have been shown to inhibit LPS-induced inflammatory cytokine release from AEC II and promote cellular proliferation (88). Small-molecule modulators targeting specific signaling pathways—such as the PKC inhibitor LXS-196 (Darovasertib), novel NOX4 inhibitor GLX351322 (25), Calcium/Calmodulin-Dependent Protein Kinase IV (CaMK4) inhibitor KN-93 (14), α7nAChR agonist PNU-282987 (141), NF-κB suppressor Bay-117082 (90), glycolysis inhibitor 3PO (42), and miR-155 inhibitor (69)—can also mitigate septic pulmonary inflammation and lung injury by modulating AEC inflammatory signaling and cytokine release. Further research on exosomes has revealed their involvement in septic pulmonary inflammation. Inhibition of AEC-derived exosome secretion reduces macrophage-mediated lung inflammation (82), while MSC-derived exosomes regulate AEC inflammatory factor release in bacterial Sepsis-Associated ALI (88). However, the full mechanistic details of these processes remain to be elucidated. In addition, inflammatory damage to AECs caused by Gram-positive bacteria is also one of the important causes of bacterial Sepsis-Associated ALI, but related therapeutic agents have not been extensively studied.

Collectively, these findings indicate that pharmacological agents, small-molecule pathway modulators, and exosome-based strategies targeting AEC-immune cell interactions and inflammatory mediator release have the potential to effectively ameliorate bacterial sepsis-induced pulmonary inflammation and the severity of bacterial Sepsis-Associated ALI. Some clinical studies have shown that the anti-inflammatory drug hydrocortisone can reduce the 28-day mortality rate in patients with severe community-acquired pneumonia (146). However, studies on bacterial sepsis-associated ARDS have not yielded significant positive results (147–149), which may be attributed to the heterogeneity between different etiologies of bacterial sepsis-associated ARDS, as well as inconsistencies in drug regimens and intervention timing. Further research is needed to explore the optimal therapeutic approaches and timing for intervention. Additionally, a retrospective analysis of the effects of drugs currently used in clinical practice, such as methylprednisolone, dexamethasone, propofol, and sufentanil, on the inflammatory response in bacterial Sepsis-Associated ALI patients could help promote further clinical research and application of these medications (Table 1).