bims-mevinf 2025-07-13 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2025–07–13
twelve papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

Reprogramming of liver metabolism during West Nile virus infection unveils novel aspects of disease pathophysiology.
Understanding the mechanisms of mitochondrial rewiring during viral infections.
Yellow Fever Virus Induces Golgi Stress and CREB3L1 Nuclear Translocation in Human A549 Cells.
Activation of store-operated calcium entry and mitochondrial respiration by enterovirus 71 is essential for efficient virus replication.
Baculovirus enhances arginine uptake and induces mitochondrial autophagy to promote viral proliferation.
Oncoviral Infection and the Significance of Reactive Oxygen Species: From Mechanisms to Therapeutic Significance.
Global transcriptome characterization of peripheral blood mononuclear cells in individuals with chronic HIV infection.
Oxidative stress is a shared characteristic of ME/CFS and Long COVID.
Fatty Acids and Inflammatory Protein Biomarkers From Coronavirus Disease 2019 Patients.
FAdV-4 infection induces selective mitochondrial autophagy.
Controlling mitochondrial membrane architecture via MIC60 determines viral replication to promote anti-viral immunity.
Oxidative stress in ARDS: mechanisms and therapeutic potential.

Mol Med. 2025 Jul 05. 31(1): 251

Reprogramming of liver metabolism during West Nile virus infection unveils novel aspects of disease pathophysiology.

Patricia Mingo-Casas, Ana-Belén Blázquez, Josefina Casas, Ana Esteban, Estela Escribano-Romero, Pedro J Sánchez-Cordón, Nereida Jiménez de Oya, Juan-Carlos Saiz, Miguel A Martín-Acebes.

   BACKGROUND: West Nile virus (WNV) is a neurotropic mosquito-borne flavivirus responsible for outbreaks of encephalitis and meningitis worldwide. About 20% of infected patients exhibit abnormal liver function tests, although the participation of this organ in the pathophysiology of the disease remains unclear. To fill this gap, this study explores changes in liver metabolism during WNV infection.
METHODS: Given the relevance of the liver as a major immune and metabolic organ, the changes in response to WNV infection were analyzed in the mouse model combining transcriptomics, lipidomics and histopathological analyses.
RESULTS: Despite the absence of detectable viral replication in the liver, infection resulted in hepatic transcriptomic reprogramming that affected inflammation, immunity, biological oxidation and lipid metabolisms. Changes in the expression of genes related to glutathione metabolism, detoxification reactions, fatty acid metabolism (fatty acid oxidation and fatty acyl-CoA biosynthesis), phospholipid synthesis (phosphatidylcholine and phosphatidylethanolamine), sphingolipid synthesis, sterol metabolism and lipid droplet organization were identified. The reduction in glutathione in the liver of infected animals was confirmed and lipidomic analyses showed an increase in the content of sphingolipids, triacylglycerols and cholesteryl esters. A decrease in the cholesterol, phosphatidylcholine and phosphatidylethanolamine levels was also observed. Moreover, histopathological findings supported the development of steatosis in one-third of WNV-infected animals.
CONCLUSIONS: The discovery of these underestimated metabolic aspects of the infection repurposes the impact of WNV on liver function. These results will contribute to a better understanding of the physiopathology of the disease and warrant special attention to liver function during WNV infection.

Keywords:  Glutathione; Infection; Lipid; Lipid droplet; Metabolism; West Nile virus

DOI:  https://doi.org/10.1186/s10020-025-01300-8
J Gen Virol. 2025 Jul;106(7):

Understanding the mechanisms of mitochondrial rewiring during viral infections.

Marta Lopez-Nieto, Nicolas Locker.

  As intracellular parasites, viruses must hijack and often rewire organelles, signalling pathways and the bioenergetics machinery of the infected cell to replicate their genome, produce viral proteins and assemble new viral particles. Mitochondria are key eukaryotic organelles often referred to as the cell's powerhouse. They control many fundamental cellular processes, from metabolism and energy production to calcium homeostasis and programmed cell death. Importantly, mitochondrial membranes are also critical sites for the integration and amplification of antiviral innate immune responses. Overall, mitochondria are therefore both supporting the virus life cycle by sustaining energy production, metabolism and synthesis of macromolecules and part of the cell's first line of defence against viruses. This review summarizes recent findings on viral manipulations of mitochondria and their functions. We explore the evolving understanding of how mitochondrial dynamics is targeted to regulate innate immunity, evasion strategies used to avoid mitochondrial-associated mechanisms that impair replication and the role of mitochondrial functions such as generating reactive oxygen species or regulating the electron transport chain during infection. Overall, we provide a comprehensive view of how viruses modulate mitochondrial function to promote replication.

Keywords:  innate immunity; mitochondria; mitochondrial unfolded protein response (UPRmt)

DOI:  https://doi.org/10.1099/jgv.0.002128
J Med Virol. 2025 Jul;97(7): e70490

Yellow Fever Virus Induces Golgi Stress and CREB3L1 Nuclear Translocation in Human A549 Cells.

María F Ferrer, Victoria Rozés-Salvador, Carla Tomatis, Pablo Thomas, Silvia Aquila, María C A M Aguiar, Eugenio A Carrera Silva, Cecilia Alvarez, Ricardo M Gómez.

  Yellow fever is an endemic disease in Africa and South America caused by the homonymous flavivirus (YFV). The disease can manifest as a febrile syndrome and, in the most severe cases, liver failure and death. Although it can be prevented by a vaccine, there is no specific treatment. Recent studies have reported a Golgi stress response following infection with other flaviviruses such as DENV or ZIKV. Here, we investigated the effects of YFV infection on the phenotype of the Golgi apparatus and the consequences of drugs that affect Golgi function in YFV replication using the human lung cancer cell line A549. We found that YFV infection causes both fragmentation of the Golgi apparatus and dispersion of the ER-Golgi intermediate compartment. Furthermore, our results showed that YFV infection increases the expression and nuclear translocation of the transcription factor CREB3L1, which is associated with the unfolded protein response and Golgi expansion. Treatment with monensin, either before or after infection, significantly reduced viral replication. This reduction was independent of IFN-Iβ secretion. Interestingly, treatment with rosuvastatin also led to a significant reduction in viral replication, but only when administered before infection. The present study is the first demonstration of a Golgi response to YFV infection and highlights a mechanism that could be targeted by future antiviral therapeutic strategies.

Keywords:  CREB3L1; IFN‐Iβ; golgi stress; monensin; rosuvastatin; yellow fever virus

DOI:  https://doi.org/10.1002/jmv.70490
mBio. 2025 Jul 08. e0371724

Activation of store-operated calcium entry and mitochondrial respiration by enterovirus 71 is essential for efficient virus replication.

Bang-Yan Hsu, Ya-Hui Tsai, Ta-Chou Weng, Szu-Hao Kung.

  Enterovirus (EV) infections disrupt cellular calcium (Ca2+) homeostasis. The EV protein 2B is localized to the endoplasmic reticulum (ER) and causes depletion of ER Ca2+ stores. This depletion coincides with a substantial increase in cytosolic Ca2+ levels driven by extracellular Ca2+ influx. However, the precise mechanism underlying this influx remains elusive. In the present study, we demonstrated that EV71 infections induce store-operated Ca2+ entry (SOCE) by activating the Ca2+ sensor stromal interaction molecule 1 (STIM1), which subsequently interacts with Orai1, a plasma membrane (PM) Ca2+ channel. This finding was supported by confocal imaging, which revealed that STIM1, typically localized in the ER, becomes active and colocalizes with Orai1 at the PM in EV71-infected cells. Pharmacological inhibition of the STIM1-Orai1 interaction and knockdown of either STIM1 or Orai1 significantly reduced virus-induced cytosolic Ca2+ levels and viral replication. Global transcriptome analysis revealed that differentially expressed genes are primarily associated with the mitochondrial electron transport chain (ETC) upon SOCE activation, contributing to enhanced ATP generation and oxygen consumption. This increase in mitochondrial Ca2+ levels is correlated with the mid-stage of virus infection. Furthermore, we demonstrated that high levels of mitochondrial Ca2+ influx led to apoptotic cell death, favoring viral release at the late stage of virus infection. Finally, SOCE-dependent EV replication was observed in a mouse intestinal organoid culture, a more physiologically relevant cell system. Our results provide valuable insights into the mechanism through which EV infections induce SOCE-mediated spatial and temporal control of Ca2+ signaling, substantially affecting the virus life cycle.IMPORTANCEHost cell Ca2+ signals play crucial roles in various steps of virus life cycles, including entry, replication, and exit. EV requires increased cytosolic Ca2+ levels for efficient replication, but the precise mechanisms underlying the association between Ca2+ levels and EV replication remain elusive. Using EV71 as a model virus, we demonstrated that EV71 infection elevated cytosolic Ca2+ levels through store-operated Ca2+ entry activation and progressive Ca2+ mobilization to mitochondria. This led to the upregulation of electron transport chain activity, which is essential for efficient virus replication and apoptotic cell death, facilitating viral release during the mid and late stages of the infectious cycle, respectively. These findings substantially enhance the understanding of how EVs co-opt host cell mechanisms to promote their life cycle. STIM1 and Orai1 may be novel targets for broad-spectrum host-directed therapeutics against EVs and other viruses that employ similar replication mechanisms.

Keywords:  SOCE; calcium flux; electron transport chain; enterovirus; viral egress; viral replication

DOI:  https://doi.org/10.1128/mbio.03717-24
PLoS Pathog. 2025 Jul 08. 21(7): e1013331

Baculovirus enhances arginine uptake and induces mitochondrial autophagy to promote viral proliferation.

Shigang Fei, Junming Xia, Yigui Huang, Minyang Zhou, Biying Xie, Yibing Kong, Luc Swevers, Jingchen Sun, Min Feng.

As obligatory intracellular parasites, viruses must rely on metabolic reprogramming of host cells to meet their replication needs. Baculovirus is an important biopesticide and a vector for the preparation of biological products. In addition, one of its representative species, Bombyx mori nucleopolyhedrovirus (BmNPV-Baculoviridae), also causes huge losses to the insect industry. In our previous study, amino acid metabolism has been found to play a crucial role in the BmNPV infection process. However, the mechanisms by which BmNPV reprograms host amino acid metabolism remains unclear. In fact, current insights in the importance of amino acid metabolism are limited to the impact of glutamine on viral infection. Therefore, unraveling the mechanism of amino acid metabolism reprogramming induced by baculovirus would advance this field of research to a great extent. In this study, targeted metabolomics revealed that the preferred amino acids of BmNPV budded virus (BV) include arginine, lysine, proline, isoleucine, histidine and others. In addition, most of the viral amino acids were found to be increased in the hemolymph of BmNPV infected silkworms at the later stage of infection, especially arginine, valine, phenylalanine and others. Furthermore, the importance of arginine for BmNPV proliferation was validated. Next, we confirmed that the expression of the arginine transporter Slc7a6 was strongly induced by BmNPV infection and that Slc7a6 could promote arginine uptake to support BmNPV proliferation in host cells. Moreover, using Slc7a6 knockout cells which eliminate extracellular arginine uptake, we confirmed that BmNPV could induce mitochondrial autophagy, thereby supplementing intracellular arginine and providing necessary amino acids for BmNPV proliferation. Overall, these findings support a model in which baculovirus (BmNPV) enhances the uptake of exogenous amino acids by inducing the expression of amino acid transporters and activating autophagy of organelles to maintain intracellular amino acid levels, thereby facilitating virus proliferation.

DOI: https://doi.org/10.1371/journal.ppat.1013331
Antioxid Redox Signal. 2025 Jul 08.

Oncoviral Infection and the Significance of Reactive Oxygen Species: From Mechanisms to Therapeutic Significance.

Ruixue Sang, Xia Zhao, Ketao Sun, Yan Zhang, Bing Luo.

  Significance: Reactive oxygen species (ROS) are a double-edged sword in the context of oncoviruses. The effects of ROS on cells depend on the cellular environment, the stage of the disease, and the specific molecular pathways involved. In general, ROS levels in oncovirus-infected cells are usually increased and produce two distinct outcomes on cancer progression and metastasis through multiple mechanisms. Therefore, identifying the relationship between ROS and tumor viruses at the molecular level is essential for cancer prevention and treatment. Recent Advances: ROS play an important role in oncoviral infection and disease progression. The excessive accumulation of ROS induces ferroptosis, which has an important role in tumor therapy and the immune microenvironment, thus providing a theoretical basis for the development of new anticancer treatment strategies. Critical Issues: This review summarizes the complex relationship between ROS and oncoviral infection, with the aim of providing a deeper understanding of tumor pathogenesis and new therapeutic strategies. Future Directions: The relationship between ROS induced by oncoviral infection and host metabolic pathways, including lipids, lipoproteins, amino acids, and polyamines. Understanding how metabolism is reprogrammed in cancer cells may elucidate the impact of these processes on viral infection and tumor progression and help develop effective treatment strategies. Antioxid. Redox Signal. 00, 000-000.

Keywords:  antioxidant defense; cancer; oncovirus; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1089/ars.2024.0868
Genomics. 2025 Jul 08. pii: S0888-7543(25)00098-9. [Epub ahead of print] 111082

Global transcriptome characterization of peripheral blood mononuclear cells in individuals with chronic HIV infection.

Han-Ying Wang, Xi Wang, Qian-Qian Zhang, Xing-Zhong Miao, Liang-Juan Chen, Li-Jun Sun, Hong-Bo Shi.

   BACKGROUND: Acquired Immune Deficiency Syndrome (AIDS), resulting from Human Immunodeficiency Virus (HIV) infection, is one of the most severe infectious diseases worldwide. The current state of prevention and control remains critical. Recent studies have increasingly highlighted the significant role of cellular metabolism in regulating immune responses and managing infections. However, whether distinct immunometabolic profiles exist among different groups infected with HIV remains to be investigated. In this study, we employed RNA-seq technology to explore the differential characterization of immune metabolism across various HIV infections.
METHODS: To investigate the metabolic differences in peripheral blood mononuclear cells (PBMCs) from HIV-infected populations, we obtained PBMCs from 18 individuals diagnosed with HIV. This cohort included four Immune Responders (IRs), five Immune Non-Responders (INRs), five typical progressors (TPs) who maintained high viral loads, and four Elite Controllers (ECs) who sustained low levels of viral replication without treatment. We conducted single-cell sequencing on the PBMCs derived from these patients and compared the results between IRs and INRs, as well as ECs and TPs.
RESULTS: Our findings revealed significant metabolic dysregulation and altered inflammatory states in INRs compared to IRs. These alterations were primarily observed in purine metabolism, oxidative phosphorylation (OXPHOS) and glycolysis pathways, as well as modifications in amino acid and fatty acid metabolism pathways. Furthermore, we identified variations within a subset of CD8+ T-cell populations characterized by high expression of GNLY, which predominantly exerts cytotoxic effects. Differences in metabolic pathways were also noted between ECs and TPs; however, these changes mainly focused on OXPHOS and pentose phosphate pathways while no significant differences were observed in glycolysis pathway.

Keywords:  HIV-1; Metabolism; Mitochondrion; Purine metabolism

DOI:  https://doi.org/10.1016/j.ygeno.2025.111082
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2426564122

Oxidative stress is a shared characteristic of ME/CFS and Long COVID.

Vishnu Shankar, Julie Wilhelmy, Ellis J Curtis, Basil Michael, Layla Cervantes, Vamsee Mallajosyula, Ronald W Davis, Michael Snyder, Shady Younis, William H Robinson, Sadasivan Shankar, Paul S Mischel, Hector Bonilla, Mark M Davis.

  Over 65 million individuals worldwide are estimated to have Long COVID (LC), a complex multisystemic condition marked by fatigue, post-exertional malaise, and other symptoms resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). With no clinically approved treatments or reliable diagnostic markers, there is an urgent need to define the molecular underpinnings of these conditions. By studying bioenergetic characteristics of peripheral blood lymphocytes in 25 healthy controls, 27 ME/CFS, and 20 LC donors, we find both ME/CFS and LC donors exhibit signs of elevated oxidative stress, especially in the memory subset. Using a combination of flow cytometry, RNA-seq, mass spectrometry, and systems chemistry analysis, we observed aberrations in reactive oxygen species (ROS) clearance pathways including elevated glutathione levels, decreases in mitochondrial superoxide dismutase protein levels, and glutathione peroxidase 4-mediated lipid oxidative damage. Strikingly, these redox pathways changes show sex-specific trends. While ME/CFS females exhibit higher total ROS and mitochondrial calcium levels, males have normal ROS levels, with pronounced mitochondrial lipid oxidative damage. In females, these higher ROS levels correlate with T cell hyperproliferation, consistent with the known role of elevated ROS in initiating proliferation. This hyperproliferation can be attenuated by metformin, suggesting this Food and Drug Administration (FDA)-approved drug as a possible treatment, as also suggested by a recent clinical study of LC patients. Moreover, these results suggest a shared mechanistic basis for the systemic phenotypes of ME/CFS and LC, which can be detected by quantitative blood cell measurements, and that effective, patient-tailored drugs might be discovered using standard lymphocyte stimulation assays.

Keywords:  ME/CFS; fatigue; long COVID; metabolism; oxidative stress

DOI:  https://doi.org/10.1073/pnas.2426564122
Immun Inflamm Dis. 2025 Jul;13(7): e70218

Fatty Acids and Inflammatory Protein Biomarkers From Coronavirus Disease 2019 Patients.

Niharika Bala, Alaa H Habib, Marianne Kozuch, Nancy D Denslow, Neha S Dhaliwal, Anna H Owings, Sarah C Glover, Abdel A Alli.

   BACKGROUND: The coronavirus disease 2019 (COVID-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and associated with systemic inflammation. Inflammation is an important process that follows infection and facilitates the body's innate immune response and repair of damaged tissue. Polyunsaturated fatty acids play an important role in the inflammatory process. These lipids can target transcription factors to modulate gene expression and protein function.
METHODS: Here, we performed a fatty acid methyl ester (FAME) analysis and immunoassays to evaluate whether differences in basal levels of different types of biomarkers can be detected in freshly frozen plasma samples from patients with and without COVID-19.
RESULTS: FAME analysis showed a decrease in arachidic acid and myristic acid, but an increase in caprylic acid, palmitic acid, and eicosenoic acid in the plasma of COVID-19 patients compared to non-COVID-19 patients. Multiple chemokines including IP-10, MCP-1, and MIP-1 beta were increased in the COVID-19 group compared to the non-COVID-19 group. Similarly, cytokines including IL-1 alpha and IL-8, and cell adhesion and inflammatory response markers including ICAM-1 and E-selectin were greater in the plasma of COVID-19 patients compared to non-COVID-19 patients.
CONCLUSIONS: A baseline signature of specific polyunsaturated fatty acids, cytokines, and chemokines present in the plasma after COVID-19 viral infection may serve as biomarkers that can be useful in various applications including determination of severity of infection, indication of disease prognosis, and consideration for therapeutic options.

Keywords:  COVID‐19; SARS‐CoV‐2; chemokines; cytokines; fatty acids; inflammation

DOI:  https://doi.org/10.1002/iid3.70218
Vet Microbiol. 2025 Jul 04. pii: S0378-1135(25)00266-4. [Epub ahead of print]308 110631

FAdV-4 infection induces selective mitochondrial autophagy.

Wenjing Dong, Peng Yang, Taiwei Ma, Yuting Liu, Yuehang Xu, Yongzhen Wang, Yunshu Li, Yujuan Niu.

  Fowl adenovirus serotype 4 (FAdV-4) is an infectious pathogen that poses a significant threat to the poultry industry. It is widely disseminated globally and is characterized by high infection and mortality rates. Mitochondria, as multifunctional dual membrane-enclosed eukaryotic organelles, maintain cellular homeostasis through various mechanisms. However, how FAdV-4 infection alters mitochondrial dynamics has not been previously established. In this study, transmission electron microscopy and immunofluorescence techniques were used to confirm that FAdV-4 infection can significantly alter mitochondrial morphology, disrupt mitochondrial fusion-fission homeostasis, and promote changes in the spatial distribution of mitochondria, causing them to gather around the nucleus. This leads to increased contact and interaction with other organelles. Preliminary analyses of the mechanistic basis for FAdV-4-mediated disruption of mitochondrial homeostasis revealed that the virus can induce selective mitophagy via the classical PINK1/Parkin signaling pathway and promote its own replication, which was confirmed by Western blotting. The novel findings regarding the ability of FAdV-4 to regulate mitochondrial morphology and function discussed in this study represent an important step forward, providing a foundation for further efforts to explore the underlying pathogenic mechanisms and to develop adjuvant approaches to preventing or managing FAdV-4 infection.

Keywords:  FAdV-4; Mitochondrial dynamics; Mitophagy; PINK1/Parkin

DOI:  https://doi.org/10.1016/j.vetmic.2025.110631
Cell Rep. 2025 Jul 01. pii: S2211-1247(25)00693-X. [Epub ahead of print] 115922

Controlling mitochondrial membrane architecture via MIC60 determines viral replication to promote anti-viral immunity.

Ichiro Katahira, Nina Liebrand, Michal Gorzkiewicz, Niklas Paul Klahm, Džiuljeta Abromavičiūtė, Julia Werner, Karina Stephanie Krings, Sarah Orywol, Tobias Lautwein, Karl Köhrer, Diran Herebian, Ertan Mayatepek, Max Anstötz, Ann Kathrin Bergmann, Arun Kumar Kondadi, Haifeng C Xu, Aleksandra A Pandyra, Takumi Kobayashi, Dirk Brenner, Thomas Floss, Ulrich Kalinke, Andreas S Reichert, Philipp A Lang.

  Virus-infected cells often exhibit dramatic cellular changes accompanied by altered mitochondrial function. The contribution of factors shaping the inner mitochondrial membrane (IMM) and cristae architecture to viral replication is insufficiently understood. Single-cell transcriptomics applying vesicular stomatitis virus infection suggests involvement of factors determining IMM architecture following infection. Consistently, inhibition of the F1FO adenosine triphosphate (ATP) synthase reduces viral replication, which is associated with oligomerization of this complex and altered IMM structure. Moreover, deletion of mitochondrial contact site and cristae organizing system (MICOS) complex by targeting MIC60 results in reduced viral replication. Generation of Mic60inv/invCD11c-Cre+ mice uncovers reduced crista junctions and viral replication in bone marrow-derived dendritic cells. Consequently, reduced viral replication in CD11c-expressing cells limits prolonged immune activation. Altogether, by linking the F1FO ATP synthase and the MICOS complex to viral replication and immune activation, we describe links between the mitochondrial structure-metabolism and the immune response against viral infection.

Keywords:  BMDC; CP: Cell biology; CP: Microbiology; MIC60; MICOS; immunometabolism; innate immunity; inner mitochondrial membrane; itaconate; mitochondria; viral infection

DOI:  https://doi.org/10.1016/j.celrep.2025.115922
Front Pharmacol. 2025 ;16 1603287

Oxidative stress in ARDS: mechanisms and therapeutic potential.

Fengyun Wang, Ruiqi Ge, Yun Cai, Mingrui Zhao, Zhen Fang, Jingguo Li, Chengzhi Xie, Mei Wang, Wanyue Li, Xiaozhi Wang.

  Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by acute lung inflammation, increased vascular permeability, and hypoxemic respiratory failure. Oxidative stress, driven by excessive reactive oxygen species (ROS), is a key contributor to ARDS pathogenesis, causing cellular damage, inflammation, and alveolar-capillary barrier disruption. This review elucidates the mechanisms of oxidative stress in ARDS, focusing on ROS production via NADPH oxidase (NOX) and mitochondria, which activate pathways like NF-κB and MAPK, promoting pro-inflammatory cytokine release. ROS-induced lipid and protein peroxidation, endothelial dysfunction, and programmed cell death (PCD), including apoptosis, pyroptosis, and ferroptosis, exacerbate lung injury. In COVID-19-related ARDS, SARS-CoV-2 spike protein amplifies mitochondrial ROS, worsening outcomes. Antioxidant therapies falter due to non-specific ROS suppression, patient heterogeneity (e.g., GSTP1 polymorphisms), and poor bioavailability. We propose a model where oxidative stress drives ARDS stages-early alveolar injury and late systemic dysfunction-suggesting targeted therapies like endothelial-specific nanoparticles or ferroptosis inhibitors. Precision medicine using biomarkers (e.g., mtDNA) and gender-specific approaches (e.g., estrogen-Nrf2 regulation) could enhance outcomes. This review bridges mechanistic gaps, critiques therapeutic failures, and advocates novel strategies like mitochondrial-targeted therapies to improve ARDS management.

Keywords:  acute lung injury (ALI); acute respiratory distress syndrome (ARDS); inflammation; oxidative stress; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3389/fphar.2025.1603287