International Journal of Molecular Sciences最新文献

{"title":"Src Homology Phosphatase 2 Disruption in Podocytes Attenuates Markers of Aristolochic Acid 1-Induced Renal Injury, Inflammation, and Fibrosis in Mice.","authors":"Ming-Fo Hsu, Fawaz G Haj","doi":"10.3390/ijms27209334","DOIUrl":"https://doi.org/10.3390/ijms27209334","url":null,"abstract":"<p><p>Aristolochic acid nephropathy (AAN) is a tubulointerstitial kidney disease caused by ingestion of aristolochic acids (AA). It is a global health concern, with no established disease-modifying therapy. Src homology phosphatase 2 (Shp2; encoded by <i>Ptpn11</i>) is a ubiquitously expressed protein tyrosine phosphatase that is implicated in renal development and function, but its contribution to AAN is unknown. Mice with podocyte-specific Shp2 disruption (<i>Ptpn11^fl/fl</i>;Pod-Cre; KO) and controls (<i>Ptpn11^fl/fl</i>) were subjected to weekly intraperitoneal injections of saline or aristolochic acid 1 (AA1, 5 mg/kg) for 4 consecutive weeks. Afterward, animals were sacrificed at 6 and 11 weeks. Renal Shp2 protein and immunofluorescence staining, including in glomeruli, were elevated following AA1 challenge. Relative to controls, KO mice exhibited attenuation of AA1-evoked changes in renal function indices, including kidney-to-body weight ratio, blood urea nitrogen, and urine albumin-to-creatinine ratio. Additionally, AA1-induced elevation in blood pressure was reduced in KO mice. At the molecular level, Shp2 deficiency was associated with significantly lower AA1-induced renal expression of inflammatory (<i>Ccl2</i>, <i>Tnf</i>) and fibrotic (<i>Acta2</i>, <i>Col1a1</i>) markers compared with controls. Histologically, AA1-induced renal interstitial collagen deposition, evaluated by picrosirius red staining, was significantly reduced in KO mice compared with controls. These findings indicate that podocyte Shp2 deficiency confers beneficial effects and attenuates AA1-induced renal injury, inflammation, and fibrosis, and identify Shp2 as a target in AAN.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prophylactic ALA Administration Attenuates Liver and Lung Injury in CLP-Induced Sepsis in Mice Through CSE/H₂S Dependent Pathways.","authors":"Aqsa Shahid, Amy Scott-Thomas, Stephen Chambers, Andrew Miller, Madhav Bhatia","doi":"10.3390/ijms27209341","DOIUrl":"https://doi.org/10.3390/ijms27209341","url":null,"abstract":"<p><p>Sepsis is a life-threatening syndrome characterized by a dysregulated host immune response to infection. Sepsis development usually results in organ dysfunction and multiple organ failure, including the liver and lungs. Alpha-lipoic acid (ALA) is a well-known anti-inflammatory agent. However, its effects on the endogenous cystathionine γ-lyase/hydrogen sulfide (CSE/H₂S) pathway during cecal ligation and puncture (CLP)-induced sepsis remain unclear. In this study, the protective effects of ALA in wild-type (WT) and CSE knockout (CSE^-/-) mice were investigated. Mice were randomly divided into six experimental groups, including (<i>a</i>) WT sham (<i>b</i>) CSE^-/- sham (<i>c</i>) WT CLP (<i>d</i>) CSE^-/- CLP (<i>e</i>) WT CLP + ALA.P and (<i>f</i>) CSE^-/- CLP + ALA.P (<i>n</i> = 8 in each group). ALA (100 mg/kg) was administered intraperitoneally one hour before CLP surgery. Eight hours after CLP induction, mice were euthanized, and blood, liver and lung tissues were collected. Body weight changes, proinflammatory cytokine and chemokine concentrations (including tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 alpha (MIP-2α), myeloperoxidase (MPO) activity, histopathological changes, plasma H₂S concentrations, and CSE expression in the liver and lung were measured. Severe liver and lung damage was characterized by markedly increased levels of MCP-1, MIP-2 α, TNF-α, and myeloperoxidase (MPO) activity, compared to WT sham control and CSE^-/- groups (<i>p</i> < 0.0001). WT CLP-induced septic mice showed liver and lung injury as evidenced by hepatocyte swelling and ballooning degeneration with liver sinusoidal congestion, as well as pulmonary intra-alveolar and interstitial edema associated with thickening of alveolar septa and leucocyte infiltration, as compared to WT sham control and CSE^-/- groups (<i>p</i> < 0.001). The WT-CLP group also showed a significant increase in hepatic and pulmonary expression of the H₂S-producing enzyme (CSE) with elevated levels of plasma H₂S concentrations, as compared to the WT sham group (<i>p</i> < 0.0001). Prophylactic ALA administration markedly improved these changes in the WT group. ALA also significantly decreased plasma H₂S concentrations and hepatic and pulmonary CSE expression as compared to the WT CLP group (<i>p</i> < 0.01). However, ALA administration did not confer additional significant protective effects in CSE^-/- mice, which supports the hypothesis that the effects of ALA are mediated through the modulation of the CSE/H₂S pathway. In conclusion, this is the first experimental evidence showing that ALA prevents sepsis-associated organ injury at least partly by the downregulation of hepatic and pulmonary cystathionine γ-lyase expression.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RETRACTED: Covarelli et al. Retinoic Acid Induced 1 and Smith-Magenis Syndrome: From Genetics to Biology and Possible Therapeutic Strategies. <i>Int. J. Mol. Sci.</i> 2025, <i>26</i>, 6667.","authors":"Jasmine Covarelli, Elisa Vinciarelli, Alessandra Mirarchi, Paolo Prontera, Cataldo Arcuri","doi":"10.3390/ijms27209366","DOIUrl":"https://doi.org/10.3390/ijms27209366","url":null,"abstract":"<p><p>The journal retracts the article titled, \"Retinoic Acid Induced 1 and Smith-Magenis Syndrome: From Genetics to Biology and Possible Therapeutic Strategies\" [...].</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13691441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Homologous Recombination: Functional Modules of Olaparib Resistance Revealed by CRISPR Screens.","authors":"Dana Dildabayeva, Diana Samarkhanova, Larissa Lezina","doi":"10.3390/ijms27209381","DOIUrl":"https://doi.org/10.3390/ijms27209381","url":null,"abstract":"<p><p>Clinical use of PARP inhibitors (PARPi), including olaparib, has improved outcomes for patients with BRCA1/2-mutant and homologous recombination (HR)-deficient tumors. However, acquired resistance remains a major limitation to their efficacy. CRISPR-Cas9 screening approaches have been developed to identify genetic drivers of PARPi resistance. However, differences in experimental conditions, library coverage, and selection design complicate comparisons across studies. In this review, we present a harmonized reanalysis of CRISPR knockout olaparib resistance screens to identify recurrent resistance-associated genes and pathways. Datasets with raw data were collected from the BioGRID ORCS database. Resistance hits identified in at least two screens were subjected to Reactome pathway-enrichment analysis and organized into functional modules. Using this approach, we identified eight modules: DNA-damage repair and replication stress; cell-cycle regulation; chromatin remodeling and histone modification; post-translational regulation; mitochondrial function; TGF-β and mTOR signaling; RNA processing and nucleocytoplasmic transport; and emerging adaptive mechanisms. Importantly, mitochondrial function genes were observed as recurrent hits, but their relation to olaparib resistance is underinvestigated. Our integrative analysis suggests that PARPi resistance is a complex, adaptive phenotype shaped by recurrent but context-dependent vulnerabilities across multiple cellular programs. This framework prioritizes candidate resistance drivers for validation and highlights directions for the design of combination therapies aimed at overcoming PARPi resistance.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Resistance: Carbapenemase Gene Profiles and Mortality in ICU Patients with Carbapenem-Resistant <i>Klebsiella pneumoniae</i> Infections.","authors":"Esra Kaya, Elif Okumuş, Elif Gülsüm Torun","doi":"10.3390/ijms27209388","DOIUrl":"https://doi.org/10.3390/ijms27209388","url":null,"abstract":"<p><p>Carbapenem-resistant <i>Klebsiella pneumoniae</i> (CRKP) causes serious infections in intensive care units (ICUs), but the relationship between carbapenemase gene profiles and mortality remains uncertain. This prospective two-center cohort included 94 adult ICU patients with clinical CRKP infection from April to September 2026. The first clinical isolate from each patient was included. <i>bla</i>_KPC, <i>bla</i>_NDM, <i>bla</i>_VIM, <i>bla</i>_IMP, <i>bla</i>_OXA-48, and <i>bla</i>_CTX-M genes were investigated by polymerase chain reaction. The primary outcome was 28-day ICU mortality; 14-day and final ICU mortality were secondary outcomes. <i>bla</i>_OXA-48, <i>bla</i>_NDM, <i>bla</i>_KPC, and <i>bla</i>_CTX-M were detected in 65 (69.1%), 49 (52.1%), 19 (20.2%), and 73 (77.7%) of isolates, respectively; <i>bla</i>_NDM and <i>bla</i>_OXA-48 co-occurred in 39 (41.5%). Fourteen-day, 28-day, and final ICU mortality rates occured in 38 (40.4%), 48 (51.1%), and 53 (56.4%), respectively. No statistically significant associations were observed between individual genes, the presence of two carbapenemase genes, or carbapenemase profiles and any mortality endpoint; adjusted analyses of 28-day ICU mortality yielded similar findings. In the exploratory Firth model, the profile effect was not significant (<i>p</i> = 0.198), whereas a higher age-adjusted Charlson Comorbidity Index and bloodstream infection or ventilator-associated pneumonia, compared with urinary tract infection, were associated with higher odds of 28-day ICU mortality. Frequent gene co-occurrence was observed; however, clinically meaningful gene-mortality associations cannot be excluded because of imprecise estimates.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Derivatives of <i>Dictyostelium</i> Differentiation-Inducing Factor-3 Promote Autophagic Flux, Mitochondrial Dysfunction and Iron-Associated Oxidative Stress.","authors":"Yue Cai, Ryu Yamada, Yuki Marugame, Satoshi Yano, Fumihiko Okumura, Haruhisa Kikuchi, Yuzuru Kubohara, Taichi Hara","doi":"10.3390/ijms27209380","DOIUrl":"https://doi.org/10.3390/ijms27209380","url":null,"abstract":"<p><p>Novel anticancer agents are needed to overcome therapeutic resistance, and autophagy represents a promising target. The chlorinated alkylphenones <i>Dictyostelium</i> differentiation-inducing factors 1 and 3 (DIF-1 and DIF-3) and their derivatives exert anti-proliferative and anti-metastatic effects; however, their molecular mechanisms remain incompletely understood. Using the GFP-LC3-RFP-LC3ΔG autophagic flux reporter, we identified Bu-DIF-3 and CP-DIF-3 as autophagy-promoting derivatives and characterized their actions principally in HeLa cells, with selected autophagy and AMP-activated protein kinase (AMPK) measurements in HAP1 cells. Both suppressed mTORC1 signaling, activated AMPK, and reduced mitochondrial membrane potential (MMP). Bu-DIF-3 additionally induced reactive oxygen species and redox stress response genes, including <i>SLC7A11</i> and <i>CHAC1</i>. <i>SLC7A11</i> induction may reflect a compensatory antioxidant response. Unlike CP-DIF-3, Bu-DIF-3 increased the FerroOrange-detectable labile Fe²⁺ signal, and deferoxamine partially restored the reduced MTT signal, supporting possible iron involvement in reduced metabolic activity. Thus, modification of the DIF-3 methoxy group modulates autophagy-promoting activity and associated stress responses. Bu-DIF-3 was associated with oxidative stress and altered labile Fe²⁺ homeostasis; whether a ferroptosis-related mechanism contributes remains unresolved. These findings provide a cellular basis for further evaluation of Bu-DIF-3 and related DIF derivatives.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune Response Gene Polymorphisms and Cervical Cancer Susceptibility.","authors":"Roksana Dwornik, Dagmara Cylwik, Katarzyna Białkowska","doi":"10.3390/ijms27209384","DOIUrl":"https://doi.org/10.3390/ijms27209384","url":null,"abstract":"<p><p>Cervical cancer (CxCa) remains one of the most common malignancies in women worldwide. Although almost all cases are associated with chronic infection with oncogenic human papillomavirus (HPV) types, not every infected woman develops the disease, indicating a significant role of genetic factors. This study reviewed 131 studies on genes related to immune system function and their impact on the risk of developing cervical cancer. The majority of the studies analyzed were conducted in Asian populations, primarily Chinese and Indian. The analysis focused in particular on polymorphisms in genes involved in the antiviral response, inflammatory processes, antigen presentation, and regulation of lymphocyte activity. Most of the evidence points to the importance of human leukocyte antigens (HLA) genes, Toll-like receptors (TLRs), interleukins (ILs), tumor necrosis factor alpha (TNF-α), and interferons (IFNs). Variants in these genes may influence the effectiveness of HPV clearance, susceptibility to persistent infection, and the risk of progression of precancerous lesions to invasive cancer. It is worth emphasizing that identifying genetic risk factors may, in the future, support the development of personalized prevention strategies, screening tests, and the assessment of the individual risk of disease. Nevertheless, most available findings warrant further validation in large and diverse populations. In summary, cervical cancer is the result of a complex interaction between HPV infection and the host's genetic predisposition. Research on immune response genes provides valuable information about the mechanisms of disease development, and may contribute to improved methods of prevention and early detection.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heparinoid Cream Restores Epidermal Barrier Homeostasis and Attenuates Type 2 Inflammation in MC903-Induced Dermatitis.","authors":"Ayaka Yasuda, Natsuko Saito-Sasaki, Reiko Hara, Yu Sawada","doi":"10.3390/ijms27209360","DOIUrl":"https://doi.org/10.3390/ijms27209360","url":null,"abstract":"<p><p>Epidermal barrier dysfunction and cutaneous inflammation are closely interconnected in inflammatory skin diseases. However, the molecular effects of heparinoid cream on inflamed skin remain incompletely understood. In this study, we investigated the effects of heparinoid cream on epidermal barrier homeostasis and cutaneous inflammation using an MC903-induced dermatitis model. Eight-week-old female BALB/c mice were treated topically with MC903 for 7 consecutive days, with or without concomitant application of heparinoid cream. Skin barrier function, histological changes, inflammatory markers, and gene expression were evaluated by transepidermal water loss measurements, histology, immunohistochemistry, quantitative PCR, and RNA sequencing. Therapeutic effects were also assessed by applying heparinoid cream after dermatitis had been established. RNA sequencing identified 816 differentially expressed genes following heparinoid cream treatment, including 146 upregulated and 670 downregulated genes. Upregulated genes were enriched in epidermal differentiation- and barrier-related pathways, whereas downregulated genes were enriched in immune and inflammatory pathways. Heparinoid cream significantly reduced transepidermal water loss and epidermal thickness, suppressed <i>Il13</i> and <i>Tslp</i> expression, and reduced epidermal KLK5 and TSLP expression. In parallel, expression of multiple epidermal differentiation- and barrier-associated genes, including members of the <i>Lce</i> family, <i>Flg</i>, and <i>Flg2</i>, was restored. Therapeutic application of heparinoid cream after establishment of dermatitis was also associated with improved barrier function, increased Flg expression, reduced Tslp mRNA expression, and decreased epidermal KLK5 and TSLP immunohistochemical staining. Secondary reanalysis of a previously published human keratinocyte RNA-seq dataset revealed changes in selected barrier- and innate immunity-associated genes following MPS treatment under non-inflammatory monolayer culture conditions. These findings demonstrate that heparinoid cream treatment is associated with concurrent improvements in epidermal barrier-related parameters and attenuation of type 2 inflammatory responses in MC903-induced dermatitis. These findings provide molecular insights into the changes associated with topical application of a heparinoid-containing formulation in inflamed skin, although the specific contribution of MPS remains to be established.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interferon-Induced Protein 6 (IFI6): Biological Functions, Molecular Mechanisms and Pathological Roles in Human Diseases.","authors":"Jingyu Yang, Yuehong Chen, Yulin Zhang, Qibing Xie, Geng Yin","doi":"10.3390/ijms27209340","DOIUrl":"https://doi.org/10.3390/ijms27209340","url":null,"abstract":"<p><p>Interferon (IFN)-induced protein 6 (IFI6) is an important member of the IFN-stimulated gene (ISG) family. It plays significant roles in anti-apoptosis, immune regulation, maintenance of mitochondrial homeostasis, antiviral defense, and tumor progression. At the molecular mechanism level, IFI6 inhibits mitochondrial membrane depolarization, cytochrome c release, and caspase activation. It also regulates the balance between B-cell lymphoma 2 (Bcl-2)/Bcl-2 interacting mediator of cell death (Bim), activates the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) pathways, and upregulates the ferroptosis-related proteins solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), thereby enhancing cell survival and proliferation through multiple pathways. In terms of immune regulation, IFI6 is associated with immune cells (such as T/B cells, etc.) and the tumor microenvironment. IFI6 regulates mitochondrial reactive oxygen species (mtROS) and mitochondrial calcium homeostasis, influencing respiratory chain assembly and metabolism. In terms of viral infection, IFI6 may inhibit the replication of multiple viruses (such as hepatitis B virus (HBV), hepatitis C virus (HCV), SARS-CoV-2, etc.) by inhibiting flavivirus-induced endoplasmic reticulum (ER) invagination, interfering with retinoic acid-inducible gene I (RIG-I)-like receptor signaling pathways, and inhibiting epidermal growth factor receptor (EGFR) kinase activity. In addition, IFI6 is highly expressed in autoimmune diseases and malignant tumors and is associated with proliferation, metastasis, and poor prognosis. In this review, we aim to highlight IFI6 as a potential key target in disease diagnosis and treatment.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Glymphatic-Meningeal Lymphatic System and Autophagy in ME/CFS and Long COVID: A Mechanistic Perspective.","authors":"Mohsen Nemat-Gorgani, Michael Anthony Jensen, Ronald Wayne Davis","doi":"10.3390/ijms27209351","DOIUrl":"https://doi.org/10.3390/ijms27209351","url":null,"abstract":"<p><p>Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Post-Acute Sequelae of SARS-CoV-2 infection (Long COVID) are complex multisystem disorders affecting 60-400 million individuals globally. They are considered post-infectious illnesses and share similar biological mechanisms, including immune dysregulation, orthostatic intolerance and cognitive dysfunction, highlighting a substantial overlap between the two conditions. Persistent fatigue, sleep dysfunction, post-exertional malaise and brain fog are among some of their most common and debilitating symptoms. Despite extensive research, they remain incurable, with no effective treatments, or simple diagnostic tests. They are increasingly understood as heterogeneous, multisystem diseases, involving neurological symptoms, with varying severities and diverse underlying biological abnormalities. More recently, the possibility of glymphatic dysfunction and autophagy impairment have been proposed as parts of the mechanistic features of the pathophysiology of these conditions, which are discussed more fully in the present perspective. With the glymphatic and meningeal lymphatic systems being operationally integrated, we will try to delineate how the metabolic waste removal mechanism afforded by this system may work together with autophagy to maintain brain homeostasis. We will provide some of the established mechanistic features of toxicity of misfolded proteins, explore their role in causing glymphatic dysfunction and impairing autophagy, and discuss the potential for therapeutic interventions.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"27 20","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149267354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}