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Keywords = autophagic dysfunction

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18 pages, 3381 KB  
Article
EPDR1 Links Fibroblast Dysfunction to Disease Severity in Idiopathic Pulmonary Fibrosis
by Jong-Uk Lee, Seung-Lee Park, Min Kyung Kim, Eunjeong Seo, Hun-Gyu Hwang, Jung Hyun Kim, Hun Soo Chang and Choon-Sik Park
Cells 2025, 14(19), 1515; https://doi.org/10.3390/cells14191515 - 28 Sep 2025
Viewed by 315
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by aberrant fibroblast activation, lysosomal dysfunction, and cellular senescence. Transcriptomic analyses have identified ependymin-related 1 (EPDR1) as a fibroblast-enriched gene in IPF, but its biological function remains unclear. EPDR1 expression was assessed in [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by aberrant fibroblast activation, lysosomal dysfunction, and cellular senescence. Transcriptomic analyses have identified ependymin-related 1 (EPDR1) as a fibroblast-enriched gene in IPF, but its biological function remains unclear. EPDR1 expression was assessed in lung fibroblasts, lung tissues, bronchoalveolar lavage fluid (BALF), and serum from IPF patients and controls using qPCR, Western blotting, ELISA, and immunohistochemistry. Lysosomal function, autophagic flux, and senescence markers were analyzed in primary fibroblasts following siRNA-mediated EPDR1 knockdown. EPDR1 was significantly upregulated in IPF-derived fibroblasts and localized to fibrotic regions enriched with α-SMA+, COL1A1+, and FN1+ myofibroblasts of IPF-derived lung tissues. EPDR1 levels were markedly elevated in the BALF and serum of IPF patients and correlated with increased mortality. IPF fibroblasts exhibited reduced lysosomal acidification and impaired autophagic flux, indicated by p62 and LC3B accumulation. EPDR1 knockdown restored lysosomal function; enhanced autophagic degradation; and reduced senescence markers, including p21, p16, and SA-β-gal activity. EPDR1 drives lysosomal dysfunction and fibroblast senescence in IPF. Its elevated expression in lung tissue and biological fluids, together with its association with prognosis, highlights EPDR1 as a potential biomarker and therapeutic target in IPF. Full article
(This article belongs to the Special Issue Advances in Pulmonary Fibrosis)
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24 pages, 1495 KB  
Review
Beyond Support Cells: Astrocytic Autophagy as a Central Regulator of CNS Homeostasis and Neurodegenerative Diseases
by Jung Ho Lee, Wonseok Chang, Sun Seek Min, Dae Yong Song and Hong Il Yoo
Cells 2025, 14(17), 1342; https://doi.org/10.3390/cells14171342 - 29 Aug 2025
Viewed by 1114
Abstract
Autophagy is a fundamental catabolic pathway critical for maintaining cellular homeostasis in the central nervous system (CNS). While neuronal autophagy has been extensively studied, growing evidence highlights the crucial roles of astrocytic autophagy in CNS physiology and pathology. Astrocytes regulate metabolic support, redox [...] Read more.
Autophagy is a fundamental catabolic pathway critical for maintaining cellular homeostasis in the central nervous system (CNS). While neuronal autophagy has been extensively studied, growing evidence highlights the crucial roles of astrocytic autophagy in CNS physiology and pathology. Astrocytes regulate metabolic support, redox balance, and neuroinflammatory responses. These functions are closely linked to autophagic activity. The disruption of astrocytic autophagy contributes to synaptic dysfunction, chronic inflammation, myelin impairment, and blood–brain barrier instability. Dysregulation of astrocytic autophagy has been implicated in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. This review summarizes the molecular mechanisms of autophagy in astrocytes and delineates its role in intercellular communication with neurons, microglia, oligodendrocytes, and endothelial cells. Furthermore, we will discuss current pharmacological approaches targeting astrocytic autophagy, with particular attention to repurposed agents such as rapamycin, lithium, and caloric restriction mimetics. Although promising in preclinical models, therapeutic translation is challenged by the complexity of autophagy’s dual roles and cell-type specificity. A deeper understanding of astrocytic autophagy and its crosstalk with other CNS cell types may facilitate the development of targeted interventions for neurodegenerative diseases. Full article
(This article belongs to the Special Issue The Role Glial Cells in Neurodegenerative Disorders)
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25 pages, 754 KB  
Review
The Impact of PCSK9 on Diabetic Cardiomyopathy: Mechanisms and Implications
by Haixia Wang, Pei Wang, Yubo Wang, Shuzhen Du, Jing Zhao and Zheng Zhang
Biomolecules 2025, 15(9), 1240; https://doi.org/10.3390/biom15091240 - 27 Aug 2025
Viewed by 913
Abstract
Diabetic cardiomyopathy (DCM) is a common and clinically relevant complication of diabetes mellitus, defined by myocardial dysfunction in the absence of overt coronary artery disease or systemic hypertension. Recent studies have identified proprotein convertase subtilisin/kexin type 9 (PCSK9) as a pivotal mediator in [...] Read more.
Diabetic cardiomyopathy (DCM) is a common and clinically relevant complication of diabetes mellitus, defined by myocardial dysfunction in the absence of overt coronary artery disease or systemic hypertension. Recent studies have identified proprotein convertase subtilisin/kexin type 9 (PCSK9) as a pivotal mediator in the pathogenesis of DCM. PCSK9 contributes not only to dyslipidemia via degradation of LDLR and consequent elevation of circulating LDL-C, but also to metabolic derangements and inflammation through interactions with receptors such as CD36 and Toll-like receptor 4 (TLR4). In DCM, PCSK9 has been shown to exacerbate inflammation and pyroptosis and is closely linked to impaired autophagic function. Elevated circulating PCSK9 has emerged as a potential biomarker for cardiovascular events in patients with type 2 diabetes mellitus (T2DM). At the same time, long-term administration of PCSK9 inhibitors (PCSK9i) has not been associated with a significant increase in incident diabetes. Furthermore, PCSK9 loss-of-function mutations have been linked to a modestly heightened risk of T2DM, underscoring its complex involvement in cardiometabolic regulation and disease. This review synthesizes current insights into the mechanistic and therapeutic roles of PCSK9 in DCM, aiming to inform precision cardiovascular risk management strategies in T2DM populations. Full article
(This article belongs to the Special Issue Cardiometabolic Disease: Molecular Basis and Therapeutic Approaches)
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24 pages, 2171 KB  
Review
Induction of Autophagy as a Therapeutic Breakthrough for NAFLD: Current Evidence and Perspectives
by Yanke Liu, Mingkang Zhang and Yazhi Wang
Biology 2025, 14(8), 989; https://doi.org/10.3390/biology14080989 - 4 Aug 2025
Viewed by 1848
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterised by hepatic steatosis in the absence of significant alcohol consumption or other specific causes of liver injury. It has become one of the leading causes of liver dysfunction worldwide. However, the precise pathophysiological [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterised by hepatic steatosis in the absence of significant alcohol consumption or other specific causes of liver injury. It has become one of the leading causes of liver dysfunction worldwide. However, the precise pathophysiological mechanisms underlying NAFLD remain unclear, and effective therapeutic strategies are still under investigation. Autophagy, a vital intracellular process in eukaryotic cells, enables the degradation and recycling of cytoplasmic components through a membrane trafficking pathway. Recent studies have demonstrated a strong association between impaired or deficient autophagy and the development and progression of NAFLD. Restoring autophagic function may represent a key approach to mitigating hepatocellular injury. Nevertheless, due to the complexity of autophagy regulation and its context-dependent effects on cellular function, therapeutic strategies targeting autophagy in NAFLD remain limited. This review aims to summarise the relationship between autophagy and NAFLD, focusing on autophagy as a central mechanism. We discuss the latest research advances regarding interventions such as diet and exercise, pharmacological therapies (including modern pharmacological therapy and plant-derived compounds), and other approaches (such as hormones, nanoparticles, gut microbiota, and vitamins). Furthermore, we briefly highlight potential autophagy-related molecular targets that may offer novel therapeutic insights for NAFLD management. Full article
(This article belongs to the Section Medical Biology)
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21 pages, 2004 KB  
Review
Interplay of Oxidative Stress, Autophagy, and Rubicon in Ovarian Follicle Dynamics: Orchestrating Ovarian Aging
by Kiyotaka Yamada, Masami Ito, Haruka Nunomura, Takashi Nishigori, Atsushi Furuta, Mihoko Yoshida, Akemi Yamaki, Kanto Shozu, Ippei Yasuda, Sayaka Tsuda, Tomoko Shima and Akitoshi Nakashima
Antioxidants 2025, 14(8), 919; https://doi.org/10.3390/antiox14080919 - 27 Jul 2025
Cited by 1 | Viewed by 1320
Abstract
Organ functions generally decline with age, but the ovary is a prototypical organ that undergoes functional loss over time. Autophagy plays a crucial role in maintaining organ homeostasis, and age-related upregulation of the autophagy inhibitor protein, Rubicon, has been linked to cellular and [...] Read more.
Organ functions generally decline with age, but the ovary is a prototypical organ that undergoes functional loss over time. Autophagy plays a crucial role in maintaining organ homeostasis, and age-related upregulation of the autophagy inhibitor protein, Rubicon, has been linked to cellular and tissue dysfunction. This review describes how granulosa cell autophagy supports follicular growth and oocyte selection and maturation by regulating cellular energy metabolism and protein quality control. We then introduce the role of selective autophagy, including mitophagy or lipophagy, in steroidogenesis and cellular remodeling during luteinization. In aged ovaries, Rubicon accumulation suppresses autophagic flux, leading to diminished oxidative-stress resilience and enhanced DNA damage. Moreover, impaired autophagy drives the accumulation of ATP citrate lyase, which correlates with poor oocyte quality and reduced ovarian reserve. Following fertilization, oocytes further upregulate autophagy to provide the energy required for blastocyst transition. Conversely, in infertility-related disorders, such as premature ovarian insufficiency, endometriosis, and polycystic ovary syndrome, either deficient or excessive autophagy contributes to disease pathogenesis. Both autophagy inhibitors (e.g., Rubicon) and activators (e.g., Beclin1) could be emerging as promising biomarkers for assessing ovarian autophagy status. Therapeutically, Rubicon inhibition by trehalose in aged ovaries and autophagy suppression by agents such as hydroxychloroquine in polycystic ovary syndrome and endometriosis hold potential. Establishing robust methods to evaluate ovarian autophagy will be essential for translating these insights into targeted treatments. Full article
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30 pages, 2885 KB  
Review
Targeting Lipophagy in Liver Diseases: Impact on Oxidative Stress and Steatohepatitis
by Jin Seok Hwang, Trang Huyen Lai and Deok Ryong Kim
Antioxidants 2025, 14(8), 908; https://doi.org/10.3390/antiox14080908 - 24 Jul 2025
Viewed by 1485
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a range of liver conditions, from simple hepatic steatosis to its more severe inflammatory form known as metabolic dysfunction-associated steatohepatitis (MASH). Despite its growing clinical significance and association with cirrhosis and cancer, there are currently few [...] Read more.
Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a range of liver conditions, from simple hepatic steatosis to its more severe inflammatory form known as metabolic dysfunction-associated steatohepatitis (MASH). Despite its growing clinical significance and association with cirrhosis and cancer, there are currently few pharmacological treatments available for MASLD, highlighting the urgent need for new therapeutic strategies. This narrative review aims to elucidate the molecular mechanisms of lipophagy in MASLD progression, emphasizing how its dysfunction contributes to hepatic steatosis and lipotoxicity. We also explore the intersection of lipophagy failure with oxidative stress and inflammation in the liver, focusing on key signaling pathways, such as mTORC1 and AMPK, and discuss the therapeutic potential of targeting these pathways by systematically reviewing the literature from PubMed, Scopus, and Google Scholar databases. Recent studies suggest that lipophagy, the selective autophagic degradation of lipid droplets, is crucial for maintaining hepatic lipid homeostasis. Indeed, some vital components of the lipophagy machinery seem to be functionally inhibited in MASLD, resulting in the accumulation of intracellular triacylglycerol (TAG), lipotoxicity, and subsequent oxidative stress, all of which contribute to disease progression. In summary, impaired lipophagy is a central pathological mechanism in MASLD, making it an important therapeutic target. A deeper understanding of these mechanisms may offer new strategic insights for combating the progression of MASLD/MASH. Full article
(This article belongs to the Special Issue Oxidative Stress and Liver Disease)
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27 pages, 1146 KB  
Review
Biological Modulation of Autophagy by Nanoplastics: A Current Overview
by Francesco Fanghella, Mirko Pesce, Sara Franceschelli, Valeria Panella, Osama Elsallabi, Tiziano Lupi, Benedetta Rizza, Maria Giulia Di Battista, Annalisa Bruno, Patrizia Ballerini, Antonia Patruno and Lorenza Speranza
Int. J. Mol. Sci. 2025, 26(15), 7035; https://doi.org/10.3390/ijms26157035 - 22 Jul 2025
Cited by 1 | Viewed by 981
Abstract
Nanoplastics (NPs), an emerging class of environmental pollutants, are increasingly recognized for their potential to interfere with critical cellular processes. Autophagy, a conserved degradative pathway essential for maintaining cellular homeostasis and adaptation to stress, has recently become a focal point of nanotoxicology research. [...] Read more.
Nanoplastics (NPs), an emerging class of environmental pollutants, are increasingly recognized for their potential to interfere with critical cellular processes. Autophagy, a conserved degradative pathway essential for maintaining cellular homeostasis and adaptation to stress, has recently become a focal point of nanotoxicology research. This review synthesizes current evidence on the interactions between NPs and autophagic pathways across diverse biological systems. Findings indicate that NPs can trigger autophagy as an early cellular response; however, prolonged exposure may lead to autophagic dysfunction, contributing to impaired cell viability and disrupted signaling. Particular attention is given to the physiochemical properties of NPs such as size, surface charge, and polymer type, which influence cellular uptake and intracellular trafficking. We also highlight key mechanistic pathways, including oxidative stress and mTOR modulation. Notably, most available studies focus almost exclusively on polystyrene (PS)-based NPs, with limited data on other types of polymers, and several reports lack comprehensive assessment of autophagic flux or downstream effects. In conclusion, a better understanding of NP–autophagy crosstalk—particularly beyond PS—is crucial to evaluate the real toxic potential of NPs and guide future research in human health and nanotechnology. Full article
(This article belongs to the Special Issue New Insights of Autophagy and Apoptosis in Cells)
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18 pages, 4436 KB  
Article
Liraglutide Attenuates Atorvastatin-Induced Hepatotoxicity by Restoring GLP-1R Expression and Activating Nrf2 and Autophagy Pathways in Wistar Rats
by Engy A. Elsiad, Hayat A. Abd El Aal, Hesham A. Salem, Mohammed F. El-Yamany and Mostafa A. Rabie
Toxics 2025, 13(7), 594; https://doi.org/10.3390/toxics13070594 - 16 Jul 2025
Cited by 1 | Viewed by 1141
Abstract
HMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvastatin and [...] Read more.
HMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvastatin and simvastatin, in particular, are most frequently associated with statin-induced liver injury, leading to treatment discontinuation. Recent research has highlighted the antioxidant and anti-inflammatory properties of glucagon-like peptide-1 receptor (GLP-1R) activation in protecting against liver injury. Nonetheless, the potential protective effects of liraglutide (LIRA), a GLP-1R agonist, against atorvastatin (ATO)-induced liver dysfunction have not been fully elucidated. In this context, the present study aimed to investigate the protective role of LIRA in mitigating ATO-induced liver injury in rats, offering new insights into managing statin-associated hepatotoxicity. Indeed, LIRA treatment improved liver function enzymes and attenuated histopathological alterations. LIRA treatment enhanced antioxidant defenses by increasing Nrf2 content and superoxide dismutase (SOD) activity, while reducing NADPH oxidase. Additionally, LIRA suppressed inflammation by downregulating the HMGB1/TLR-4/RAGE axis and inhibiting the protein expression of pY323-MAPK p38 and pS635-NFκB p65 content resulting in decreased proinflammatory cytokines (TNF-α and IL-1β). Furthermore, LIRA upregulated GLP-1R gene expression and promoted autophagic influx via the activation of the pS473-Akt/pS486-AMPK/pS758-ULK1/Beclin-1 signaling cascade, along with inhibiting apoptosis by reducing caspase-3 content. In conclusion, LIRA attenuated ATO-induced oxidative stress and inflammation via activation of the Nrf-2/SOD cascade and inhibition of the HMGB1/TLR-4/RAGE /MAPK p38/NFκB p65 axis. In parallel, LIRA stimulated autophagy via the AMPK/ULK1/Beclin-1 axis and suppressed apoptosis, thus restoring the balance between autophagy and apoptosis. Full article
(This article belongs to the Section Drugs Toxicity)
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30 pages, 1700 KB  
Review
The Inflammatory Nexus: Unraveling Shared Pathways and Promising Treatments in Alzheimer’s Disease and Schizophrenia
by Aurelio Pio Russo, Ylenia Pastorello, Lóránd Dénes, Klara Brînzaniuc, Jerzy Krupinski and Mark Slevin
Int. J. Mol. Sci. 2025, 26(13), 6237; https://doi.org/10.3390/ijms26136237 - 27 Jun 2025
Viewed by 1167
Abstract
Alzheimer’s disease (AD) and schizophrenia are traditionally considered distinct clinical entities, yet growing evidence highlights substantial overlap in their molecular and neuroinflammatory pathogenesis. This review explores current insights into the shared and divergent mechanisms underlying these disorders, with emphasis on neuroinflammation, autophagy dysfunction, [...] Read more.
Alzheimer’s disease (AD) and schizophrenia are traditionally considered distinct clinical entities, yet growing evidence highlights substantial overlap in their molecular and neuroinflammatory pathogenesis. This review explores current insights into the shared and divergent mechanisms underlying these disorders, with emphasis on neuroinflammation, autophagy dysfunction, blood–brain barrier (BBB) disruption, and cognitive impairment. We examine key signaling pathways, particularly spleen tyrosine kinase (SYK), the mechanistic (or mammalian) target of rapamycin (mTOR), and the S100 calcium-binding protein B (S100B)/receptor for advanced glycation end-products (RAGE) axis, that link glial activation, excitatory/inhibitory neurotransmitter imbalances, and impaired proteostasis across both disorders. Specific biomarkers such as S100B, matrix metalloproteinase 9 (MMP9), and soluble RAGE show promise for stratifying disease subtypes and predicting treatment response. Moreover, psychiatric symptoms frequently precede cognitive decline in both AD and schizophrenia, suggesting that mood and behavioral disturbances may serve as early diagnostic indicators. The roles of autophagic failure, cellular senescence, and impaired glymphatic clearance are also explored as contributors to chronic inflammation and neurodegeneration. Current treatments, including cholinesterase inhibitors and antipsychotics, primarily offer symptomatic relief, while emerging therapeutic approaches target upstream molecular drivers, such as mTOR inhibition and RAGE antagonism. Finally, we discuss the future potential of personalized medicine guided by genetic, neuroimaging, and biomarker profiles to optimize diagnosis and treatment strategies in both AD and schizophrenia. A greater understanding of the pathophysiological convergence between these disorders may pave the way for cross-diagnostic interventions and improved clinical outcomes. Full article
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26 pages, 959 KB  
Review
Autophagy and Alzheimer’s Disease: Mechanisms and Impact Beyond the Brain
by Zaw Myo Hein, Thirupathirao Vishnumukkala, Barani Karikalan, Aisyah Alkatiri, Farida Hussan, Saravanan Jagadeesan, Mohd Amir Kamaruzzaman, Muhammad Danial Che Ramli, Che Mohd Nasril Che Mohd Nassir and Prarthana Kalerammana Gopalakrishna
Cells 2025, 14(12), 911; https://doi.org/10.3390/cells14120911 - 16 Jun 2025
Cited by 2 | Viewed by 2936
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by neuronal loss, cognitive decline, and pathological hallmarks such as amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. Recent evidence highlights autophagy as a pivotal mechanism in cellular homeostasis, mediating the clearance of misfolded proteins [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by neuronal loss, cognitive decline, and pathological hallmarks such as amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. Recent evidence highlights autophagy as a pivotal mechanism in cellular homeostasis, mediating the clearance of misfolded proteins and damaged organelles. However, impaired autophagy contributes significantly to AD pathogenesis by disrupting proteostasis, exacerbating neuroinflammation, and promoting synaptic dysfunction. This review aims to scrutinize the intricate relationship between autophagy dysfunction and AD progression, explaining key pathways including macroautophagy, chaperone-mediated autophagy (CMA), and selective autophagy processes such as mitophagy and aggrephagy. This further extends the discussion beyond the central nervous system, evaluating the role of hepatic autophagy in Aβ clearance and systemic metabolic regulation. An understanding of autophagy’s involvement in AD pathology via various mechanisms could give rise to a novel therapeutic strategy targeting autophagic modulation to mitigate disease progression in the future. Full article
(This article belongs to the Special Issue Biological Mechanisms in the Treatment of Neuropsychiatric Diseases)
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21 pages, 16995 KB  
Article
Vitamin D Attenuates Hepatic Sinusoidal Capillarization in Type 2 Diabetes Mellitus– Metabolic Dysfunction-Associated Fatty Liver Disease via Dual Autophagy Activation and Pyroptosis Suppression in Liver Sinusoidal Endothelial Cells
by Panpan Jiang, Yang Liu, Juxiang Liu and Jinxing Quan
Biomedicines 2025, 13(6), 1459; https://doi.org/10.3390/biomedicines13061459 - 13 Jun 2025
Viewed by 864
Abstract
Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD) is closely associated with type 2 diabetes mellitus (T2DM), where T2DM serves as a crucial driving factor for MAFLD progression. While vitamin D (VD) demonstrates protective effects against MAFLD, the underlying mechanisms through which it influences [...] Read more.
Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD) is closely associated with type 2 diabetes mellitus (T2DM), where T2DM serves as a crucial driving factor for MAFLD progression. While vitamin D (VD) demonstrates protective effects against MAFLD, the underlying mechanisms through which it influences MAFLD-related liver sinusoidal endothelial cell (LSEC) capillarization remain to be elucidated. This study aimed to explore how vitamin D ameliorates LSEC capillarization in T2DM-associated MAFLD. Methods: Culture human liver sinusoidal endothelial cells (HLSECs) according to the established protocol. After 1,25(OH)2D3 intervention in high glucose (HG)-induced HLSECs, determine the changes in liver sinusoidal capillarization-related proteins (LN, PLVAP), autophagy and pyroptosis levels. Observe the changes in cell lipid accumulation and fenestration structures. After adding Bafilomycin A1, MCC950, compound C and rapamycin to HLSECs, explore the therapeutic mechanism of 1,25(OH)2D3. After supplementing VD to MAFLD model mice, further verify the therapeutic mechanism of VD on MAFLD. Results: HG can induce the capillarization and lipid accumulation of HLSEC, increase the level of pyroptosis, and simultaneously reduce the autophagy level. Vitamin D alleviated high-glucose-induced pyroptosis (by suppressing GSDMD/NLRP3) and autophagic inhibition by activating the AMPK-mTOR axis (upregulating p-AMPK and downregulating mTOR), and improved lipid accumulation and hepatic sinusoidal capillarization. In the mouse model of MAFLD, VD supplementation can induce autophagy, inhibit pyroptosis and capillarization, and improve MAFLD. Conclusions: These results demonstrate, for the first time, that VD mitigates LSEC dysfunction through dual mechanisms: activating AMPK-dependent autophagy and inhibiting pyroptosis, providing a therapeutic rationale for VD in treating MAFLD-related sinusoidal pathology. Full article
(This article belongs to the Section Cell Biology and Pathology)
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30 pages, 1318 KB  
Review
Pathogenesis and Therapeutic Perspectives of Tubular Injury in Diabetic Kidney Disease: An Update
by Jiamian Geng, Sijia Ma, Hui Tang and Chun Zhang
Biomedicines 2025, 13(6), 1424; https://doi.org/10.3390/biomedicines13061424 - 10 Jun 2025
Viewed by 2304
Abstract
Diabetic kidney disease (DKD), a well-characterized microvascular complication associated with the progression of diabetes mellitus, has been identified as the leading etiological factor contributing to the global burden of end-stage kidney disease (ESKD). Historically, DKD research has predominantly centered on glomerular mechanisms; however, [...] Read more.
Diabetic kidney disease (DKD), a well-characterized microvascular complication associated with the progression of diabetes mellitus, has been identified as the leading etiological factor contributing to the global burden of end-stage kidney disease (ESKD). Historically, DKD research has predominantly centered on glomerular mechanisms; however, recent studies have increasingly emphasized the critical role of tubular dysfunction. Extensive evidence has elucidated the key pathological drivers of tubular injury in DKD, encompassing metabolic dysregulation, pro-inflammatory signaling pathways, diverse cellular stress responses, and epithelial–mesenchymal transition (EMT). Furthermore, emerging mechanistic studies reveal that autophagic flux impairment and epigenetic memory formation collaboratively drive cellular senescence in DKD. Regarding the treatment of DKD, various hypoglycemic drugs, as well as hypotensive drugs, and microcirculatory improvers have garnered significant attention. Recently, stem cell-based interventions and precision gene editing techniques have unveiled novel therapeutic paradigms for DKD, fundamentally expanding the treatment arsenal beyond conventional pharmacotherapy. This review synthesizes updated insights into the pathogenesis of tubular injury in DKD and highlights promising therapeutic strategies for managing this condition. Full article
(This article belongs to the Special Issue Diabetes: Comorbidities, Therapeutics and Insights (2nd Edition))
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30 pages, 1993 KB  
Review
Synergistic Autophagy-Related Mechanisms of Protection Against Brain Aging and AD: Cellular Pathways and Therapeutic Strategies
by Bogdan Cordos, Amelia Tero-Vescan, Ian N. Hampson, Anthony W. Oliver and Mark Slevin
Pharmaceuticals 2025, 18(6), 829; https://doi.org/10.3390/ph18060829 - 1 Jun 2025
Cited by 2 | Viewed by 2683
Abstract
Brain aging is driven by interconnected processes, including impaired autophagy, chronic inflammation, mitochondrial dysfunction, and cellular senescence, all of which contribute to neurovascular decline and neurodegenerative diseases such as Alzheimer’s disease (AD). Targeting these mechanisms simultaneously offers a promising therapeutic approach. This review [...] Read more.
Brain aging is driven by interconnected processes, including impaired autophagy, chronic inflammation, mitochondrial dysfunction, and cellular senescence, all of which contribute to neurovascular decline and neurodegenerative diseases such as Alzheimer’s disease (AD). Targeting these mechanisms simultaneously offers a promising therapeutic approach. This review explores the rationale for combining metformin, benzimidazole derivatives, phosphodiesterase-5 (PDE5), and acetylsalicylic acid (ASA) as a multi-targeted strategy to restore proteostasis, reduce senescence-associated secretory phenotype (SASP) factors, and enhance mitochondrial and lysosomal function. Metformin activates AMP-activated protein kinase (AMPK) and promotes autophagy initiation and chaperone-mediated autophagy, whilst benzimidazole derivatives enhance lysosomal fusion through JIP4–TRPML1 pathways independently of mTOR signaling; and ASA augments autophagic flux while suppressing NF-κB-driven inflammation and promoting specialized pro-resolving mediator pathways. This combinatorial approach targets both upstream autophagy initiation and downstream autophagosome–lysosome fusion, while concurrently attenuating inflammation and cellular senescence. Patient stratification based on the biomarkers of autophagy impairment, inflammation, and metabolic dysfunction could optimize therapeutic responses. While this strategy shows strong preclinical promise, careful attention to timing, dosing, and cell-specific responses is crucial to maximize benefits and avoid adverse effects. Future studies integrating biomarker-guided precision medicine frameworks are essential to validate the potential of this therapeutic combination in preventing or slowing cognitive decline and promoting healthy brain aging. Full article
(This article belongs to the Section Biopharmaceuticals)
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26 pages, 4820 KB  
Review
Autophagy—Unlocking New Dimensions in the Pathology and Treatment of Depression
by Qiang Luo, Yulong Zhao, Peng Ren, Xu Liu, Yingjian Chen, Qianru Ying and Junjie Zhou
Cells 2025, 14(11), 795; https://doi.org/10.3390/cells14110795 - 28 May 2025
Cited by 3 | Viewed by 1676
Abstract
Depression is a widespread mental disorder whose impact on an individual’s health extends far beyond the psychological dimension. As a disease with a significant burden, the effective treatment of depression has become a major challenge for global public health. Although several hypotheses have [...] Read more.
Depression is a widespread mental disorder whose impact on an individual’s health extends far beyond the psychological dimension. As a disease with a significant burden, the effective treatment of depression has become a major challenge for global public health. Although several hypotheses have been proposed for the pathogenesis of depression, its pathophysiological mechanisms remain complex and not yet fully understood. Recent studies suggest that dysfunctional autophagy may play an important role in the development of depression. Autophagy, as an important intracellular degradation mechanism, maintains neuronal function and health by removing excess proteins and damaged organelles. Current evidence suggests that the regulation of autophagic processes may provide new potential targets for the treatment of depression. In this paper, we review the pharmacological mechanisms of autophagy by different antidepressant drugs and the abnormal changes in autophagy in patients with depression and in multiple models. Importantly, we focus on the role of autophagy in different pathological mechanisms of depression and discuss current limitations as well as potential directions for future research. Full article
(This article belongs to the Collection Feature Papers in Autophagy)
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23 pages, 2239 KB  
Review
Molecular Mechanisms of Epithelial–Mesenchymal Transition in Retinal Pigment Epithelial Cells: Implications for Age-Related Macular Degeneration (AMD) Progression
by Na Wang, Yaqi Wang, Lei Zhang, Wenjing Yang and Songbo Fu
Biomolecules 2025, 15(6), 771; https://doi.org/10.3390/biom15060771 - 27 May 2025
Cited by 1 | Viewed by 1346
Abstract
Age-related macular degeneration (AMD), the leading cause of irreversible blindness worldwide, represents a complex neurodegenerative disorder whose pathogenesis remains elusive. At the core of AMD pathophysiology lies the retinal pigment epithelium (RPE), whose epithelial–mesenchymal transition (EMT) has emerged as a critical pathological mechanism [...] Read more.
Age-related macular degeneration (AMD), the leading cause of irreversible blindness worldwide, represents a complex neurodegenerative disorder whose pathogenesis remains elusive. At the core of AMD pathophysiology lies the retinal pigment epithelium (RPE), whose epithelial–mesenchymal transition (EMT) has emerged as a critical pathological mechanism driving disease progression. This transformative process, characterized by RPE cell dedifferentiation and subsequent extracellular matrix remodeling, is orchestrated through a sophisticated network of molecular interactions and cellular signaling cascades. Our review provides a comprehensive analysis of the molecular landscape underlying RPE EMT in AMD, with particular emphasis on seven interconnected pathological axes: (i) oxidative stress and mitochondrial dysfunction, (ii) hypoxia-inducible factor signaling, (iii) autophagic flux dysregulation, (iv) chronic inflammatory responses, (v) complement system overactivation, (vi) epigenetic regulation through microRNA networks, and (vii) key developmental signaling pathway reactivation. Furthermore, we evaluate emerging therapeutic strategies targeting EMT modulation, providing a comprehensive perspective on potential interventions to halt AMD progression. By integrating current mechanistic insights with therapeutic prospects, this review aims to bridge the gap between fundamental research and clinical translation in AMD management. Full article
(This article belongs to the Section Molecular Biology)
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