Regulated cell death is a form of cell death that is actively controlled by biomolecules. Several studies have shown that regulated cell death plays a key role after spinal cord injury. Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords. Autophagy, a complex form of cell death that is interconnected with various regulated cell death mechanisms, has garnered significant attention in the study of spinal cord injury. This injury triggers not only cell death but also cellular survival responses. Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis, ferroptosis, and autophagy. Therefore, this review aims to comprehensively examine the mechanisms underlying regulated cell deaths, the signaling pathways that modulate these mechanisms, and the potential therapeutic targets for spinal cord injury. Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury. Moreover, a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.

African swine fever (ASF) is an acute, highly fatal hemorrhagic disease of domestic and wild pigs caused by African swine fever virus (ASFV). ASFV, a large double-stranded DNA virus of the Asfarviridae family, is highly infectious and pathogenic. Through modulation of host apoptosis and autophagy pathways, the virus subverts innate immune surveillance to promote its replication and dissemination. Following ASFV infection, domestic pigs may exhibit 100 % morbidity and mortality rates with highly virulent strains, constituting a major threat to the global pork industry. Nowadays, ASF is listed as a notifiable terrestrial animal disease by the World Organisation for Animal Health (WOAH). Therefore, elucidating ASFV's pathogenic mechanisms, particularly its molecular regulation of apoptosis and autophagy, is crucial for developing effective ASF control and prevention strategies. This review comprehensively summarizes the pathogenic mechanisms of ASFV, with particular focus on the autophagy-apoptosis crosstalk and viral manipulation of these cellular processes. These insights not only improve our understanding of ASFV-mediated immune evasion mechanisms but also provide valuable references for developing ASF control strategies targeting apoptosis and autophagy pathways.

Repeated exposure to airborne terrestrial natural minerals may cause pneumoconiosis and lung cancer, among which iron sulfide is identified as an aggravating factor. In the biological system, iron-sulfur cluster is an inorganic cofactor that is evolutionarily conserved in all the living organisms. Whereas ferrous iron catalyzes the generation of hydroxyl radicals, sulfur is indispensable as a component of antioxidants, such as glutathione. Imbalanced redox homeostasis contributes to oxidative stress, causing ferroptosis, an iron-dependent regulated necrosis characterized by lipid peroxidation, resulting in various disorders. We undertook this study to understand the cellular regulatory mechanisms against major terrestrial minerals containing iron and sulfur from the viewpoint of cellular redox. We used fundamental iron sulfide minerals collected from natural sources to treat human macrophage and fibroblast cells and investigated the biological responses. Alterations in sulfane sulfur, glutathione and iron have been analyzed using either specific fluorescent probes or inductively coupled plasma mass spectrometry. Iron sulfide microparticles with high Fe/S ratio (pyrrhotite; Fe1-XS) induced more reactive sulfane species and glutathione, with less catalytic iron inside cells, whereas the mineral with low Fe/S ratio (pyrite; FeS2) exhibited the opposite effects. Notably both showed cytotoxicity, where pyrite caused ferroptosis but pyrrhotite led to non-ferroptotic disruption. Furthermore, assimilated cellular excess iron was secreted via CD63(+) exosome containing iron-loaded ferritin to the extracellular space with higher iron content in pyrrhotite. Our findings suggest that iron and sulfur work complementarily in maintaining intracellular redox homeostasis, which would be crucial to understand the associated pathology.

Disruption in the homeostasis of anions within organelles in cancer cells by synthetic small-molecule anion transporters may lead to significant inhibition in the proliferation of cancer cells. However, the specific impact of anion transporters on organelles, in particular on the Golgi apparatus remains to be explored. In this study, we designed and synthesized a novel series of Golgi-targeting anion transporters composed of squaramido moiety for transporting chloride anions and benzenesulfonamido group for targeting the Golgi apparatus. These compounds were able to efficiently facilitate the transport of anions across liposomal and cellular membranes, and exhibit significant cytotoxicity toward several selected cancer cells. Among them, compound 10 was the most active in efficiently disrupting the homeostasis of chloride anions specifically within the Golgi apparatus. This disruption led to profound perturbations in the structure and function of the Golgi apparatus, and triggered Golgiphagy and further apoptosis. More importantly, compound 10 displayed potent antitumor efficacy toward HepG2 xenograft mouse models, with low toxicity and minimal adverse effects on major organs. The present findings underscore the critical role of regulating the homeostasis of chloride anions within the Golgi apparatus in triggering the Golgiphagy and apoptosis of cancer cells, and thus provide a new strategy for the discovery of innovative chemotherapy for cancers.

Levodopa-induced dyskinesia (LID) represents a significant complication associated with the long-term administration of levodopa (L-DOPA) for the treatment of Parkinson's disease (PD). This review examines the critical role of ΔFosB, a transcription factor, in the pathogenesis of LID and explores potential therapeutic interventions. ΔFosB accumulates within the striatum in response to chronic dopaminergic stimulation, thereby driving maladaptive changes that culminate in dyskinesia. Its persistent expression modifies gene transcription, influencing neuronal plasticity and contributing to the sustained presence of dyskinetic movements. This study explains how ΔFosB functions at the molecular level, focusing on its connections with dopamine D1 receptors, the cAMP/PKA signaling pathway, and its regulatory effects on downstream targets such as DARPP-32 and GluA1 AMPA receptor subunits. Additionally, it examines how neuronal nitric oxide synthase (nNOS) affects ΔFosB levels and the development of LID. This review also considers the interactions between ΔFosB and other signaling pathways, such as ERK and mTOR, in the context of LID and striatal plasticity. Emerging therapeutic strategies targeting ΔFosB and its associated pathways include pharmacological interventions like ranitidine, 5-hydroxytryptophan, and carnosic acid. Furthermore, this study addresses the role of JunD, another component of the AP-1 transcription factor complex, in the pathogenesis of LID. Understanding the molecular mechanisms by which ΔFosB contributes to LID offers promising avenues for developing novel treatments that could mitigate dyskinesia and improve the quality of life for PD patients undergoing long-term L-DOPA therapy.

Emerging research has confirmed the crucial role of autophagy, an endogenous repair mechanism, in various blast injuries. However, its role in explosive ocular injury (EOI) under microgravity (MG) and normal gravity (NG) environments remains poorly understood. Therefore, this study aimed to investigate the changes in retinal lesions and retinal autophagy over time following EOI under both NG and MG environments. This study employed the hind-limb unloading model in Sprague-Dawley (SD) rats to simulate MG conditions and used self-made device with compressed gas to induce EOI. SD rats were randomly divided into six groups as follows: normal gravity control group (NG + non-EOI group), normal gravity model group at 1 day post-EOI injury (NG + EOI 1dpi group, n = 20), normal gravity model group at 7 days post-EOI injury (NG + EOI 7dpi group, n = 20), microgravity control group (MG + non-EOI group), microgravity model group at 1 day post-EOI injury (MG + EOI 1dpi group, n = 20), and microgravity model group at 7 days post-EOI injury (MG + EOI 7dpi group, n = 20). Evaluations of ocular health (gross pathology and histology), and retinal autophagy (histology and WB) were conducted before EOI, as well as at 1 and 7 days following EOI. Compared to the NG + non-EOI group, the NG + EOI group rats exhibited significant increases in autophagy-related proteins and genes in the retina, including Beclin1, LC3Ⅱ/LC3Ⅰ, ATF4, GRP78, CHOP, ATG5, and ATG7, along with a decrease in p62, indicating an elevation in retinal autophagy and ER-phagy levels. Retinal lesions, disintegration, and autophagosomes in the ganglion cell layer (GCL) and photoreceptor inner/outer segment layers (PISL/POSL) diminished over time in the NG + EOI group rats. Meanwhile, the MG + EOI group rats exhibited more severe retinal lesions and disintegration, along with an increased number of autophagosomes in the GCL and PISL/POSL, with these symptoms worsening over time compared to the MG + non-EOI group. Compared to the MG + non-EOI group, the MG + EOI group rats exhibited significant decreases in autophagy-related proteins and genes in the retina, including Beclin1, LC3Ⅱ/LC3Ⅰ, ATF4, GRP78, CHOP, ATG5, and ATG7, along with an increase in p62, suggesting a reduction in retinal autophagy levels. Taken together, retinal autophagy and ER-phagy may serve as a self-protective mechanism following EOI under NG conditions. However, under MG conditions, EOI may disrupt this protective mechanism, potentially causing irreversible retinal damage and increasing the risk of blindness in astronauts.

Osteoporosis (OP) is a prevalent skeletal disorder characterized by an imbalance between bone resorption and bone formation, resulting in a significant global burden. Previous research utilizing bioinformatics analysis has identified MAP4K2, SPI1, and CTSD as hub genes associated with OP. In this current investigation, we have successfully established a differential expression system of MAP4K2, SPI1, and CTSD in rat bone marrow mesenchymal stem cells (BMSCs) through transfection techniques. Additionally, the CCK-8 assay was employed to assess cell proliferation, while the alkaline phosphatase (ALP) activity assay and ALP staining assay were utilized to evaluate osteogenic differentiation. Alizarin red staining was employed to detect mineralization of BMSCs. Furthermore, the expression of relevant genes and molecules associated with the MAPK signaling pathway, autophagy, and apoptosis in the sera of rat BMSCs were examined using quantitative real-time polymerase chain reaction (qRT-PCR). The purpose of this study was to preliminarily investigate whether MAP4K2, SPI1, and CTSD have an effect on the osteogenic capacity of rat BMSCs and whether these genes, when differentially expressed, affect the expression of related genes in the MAPK, autophagy, and apoptosis signaling pathways and thus the osteogenic function of BMSCs. In summary, the findings of this study indicate that MAP4K2 and CTSD exert significant influence on the proliferation, osteogenic differentiation, and mineralization processes of rat BMSCs cells. Furthermore, these proteins may contribute to the development of OP through their involvement in the regulation of autophagy and apoptosis. Conversely, our investigation did not reveal any discernible impact of SPI1 on OP-related phenotypes. Consequently, this research serves as a fundamental basis for further exploration of potential therapeutic targets for the treatment of OP.

Proteostasis (protein homeostasis) refers to the general biological process that maintains the proper balance between the synthesis of proteins, their folding, trafficking, and degradation. It ensures proteins are functional, locally distributed, and appropriately folded inside cells. Genetic information enclosed in mRNA is translated into proteins. To ensure newly synthesized proteins take on the exact three-dimensional conformation, molecular chaperones assist in proper folding. Misfolded proteins can be refolded or targeted for elimination to stop aggregation. Cells utilize different degradation pathways, for instance, the ubiquitin-proteasome system, the autophagy-lysosome pathway, and the unfolded protein response, to degrade unwanted or damaged proteins. Quality control systems of the cell monitor the folding of proteins. These checkpoint mechanisms are aimed at degrading or refolding misfolded or damaged proteins. Under stress response pathways, such as heat shock response and unfolded protein response, which are triggered under conditions that perturb proteostasis, the capacity for folding is increased, and degradation pathways are activated to help cells handle stressful conditions. The deregulation of proteostasis is implicated in a variety of illnesses, comprising cancer, metabolic diseases, cardiovascular diseases, and neurological disorders. Therapeutic strategies with a deeper insight into the mechanism of proteostasis are crucial for the treatment of illnesses linked with proteostasis and to support cellular health. Thus, proteostasis is required not only for the maintenance of cellular homeostasis and function but also for proper protein function and prevention of injurious protein aggregation. In this review, we have covered the concept of proteostasis, its mechanism, and how disruptions to it can result in a number of disorders.

The role of autophagy in cholangiocarcinogenesis and its development is intricate. Autophagy has a dual role in cholangiocarcinoma, and understanding the function and mechanism of autophagy in cholangiocarcinoma is pivotal in guiding therapeutic approaches to its treatment in clinical settings. Recent studies have revealed that autophagy is involved in the complex biological behavior of cholangiocarcinoma. In this review, we have summarized the genes and drugs that would promote or inhibit autophagy, leading to change in cellular behaviors of cholangiocarcinoma, including apoptosis, proliferation, invasion and migration, and influence its cellular drug resistance. In addition, we concluded the signaling pathways modulating autophagy in cholangiocarcinoma cells, including PI3K/AKT/mTOR,p38MAPK,AMPK/mTOR,LKB1-AMPK, and AKT/WNK1, and ERK signaling pathways, which subsequently impacting apoptosis, death, migration, invasion, and proliferation. In conclusion, we would like that we can provide ideas for future cholangiocarcinoma treatment by comprehensively summarizing the latest studies on the relationship between autophagy and cholangiocarcinoma, including the factors affecting autophagy and related signaling pathways.

Host-directed therapies (HDTs) have been investigated as a potential solution to combat intracellular and drug-resistant bacteria. HDTs stem from extensive research on the intricate interactions between the host and intracellular bacteria, leading to a treatment approach that relies on immunoregulation. To improve the bioavailability and safety of HDTs, researchers have utilized diverse drug delivery systems (DDS) to encapsulate and transport therapeutic agents to target cells. In this review, we first introduce the three mechanisms of bactericidal action and intracellular bacterial evasion: autophagy, reactive oxygen species (ROS), and inflammatory cytokines, with a particular focus on autophagy. Special attention is given to the detailed mechanism of xenophagy in clearing intracellular bacteria, a crucial selective autophagy process that specifically targets and degrades intracellular pathogens. Following this, we present the application of DDS to modulate these regulatory methods for intracellular bacteria elimination. By integrating insights from immunology and nanomedicine, this review highlights the emerging role of DDS in advancing HDTs for intracellular bacterial infections and paving the way for innovative therapeutic interventions.

Human periodontal ligament cells (hPDLCs) play a pivotal role in periodontal tissue remodelling, a process essential for orthodontic tooth movement (OTM). Autophagy, a survival mechanism under cellular stress, is induced by nutrient deprivation and impacts hPDLC function. This study aimed to explore the role of autophagy in the adaptive response of hPDLCs to nutritional stress, an environment simulating conditions during OTM.

Nutrient deprivation in hPDLCs was modelled through serum starvation. Autophagy levels and relevant markers were assessed using electron microscopy, protein assays, and gene expression analyses. Emphasis was placed on adenosine monophosphate-activated protein kinase (AMPK) signalling, specifically phosphorylation of AMPKα at Thr172, as a regulatory node in autophagy induction. Loss- and gain-of-function approaches were utilized to investigate the role of Thr172 in AMPK-mediated autophagy under nutrient stress.

Findings indicated a marked increase in reactive oxygen species-mediated autophagy in hPDLCs under nutrient deprivation. This process was significantly regulated by AMPK activation through Thr172 phosphorylation, establishing AMPK as a critical factor in autophagy induction during cellular adaptation to nutritional stress.

Nutritional stress enhances reactive oxygen species-mediated autophagy in hPDLCs via AMPK signalling, underscoring the role of autophagy in cellular adaptation during OTM. Targeting the AMPK pathway could provide novel insights for optimizing orthodontic treatment by leveraging cellular adaptive mechanisms.

Understanding the molecular mechanisms underlying autophagy in hPDLCs opens potential therapeutic pathways to improve OTM outcomes. Modulating autophagy may lead to advances in orthodontic therapies that facilitate periodontal tissue remodelling, enhancing clinical effectiveness.

Autophagy, a conserved cellular mechanism which detoxifies and degrades intracellular structures or biomolecules, has been identified as an important factor in the progression of human breast cancer and the development of treatment resistance. Non-coding RNAs (ncRNAs), a broad family of RNA, have the ability to influence various processes, including autophagy, due to their diverse downstream targets. ncRNAs play an important role in suppressing or activating autophagy by targeting autophagy-triggering components such as the ULK1 complex, Beclin1, and ATGs. Recent research has uncovered the intricate regulatory networks that govern autophagy dynamics, with ncRNAs emerging as key participants in this network. miRNAs, lncRNAs, and circRNAs are the three subfamilies of ncRNAs that have the most well-known interactions with autophagy, particularly macroautophagy. The high prevalence of breast cancer necessitates research into finding new biological processes that can help in early detection as well as enhance the effectiveness of treatment. The positive/negative link between autophagy and ncRNAs can be exploited as a supplementary therapy to improve sensitivity to treatment in breast cancer. This review investigates the regulatory roles of ncRNAs, particularly microRNAs (miRNAs), in modifying autophagy pathways in human breast cancer progression and treatment. However, future studies and clinical practice are needed to determine the most relevant microRNAs as biomarkers and also to better understand their role in breast cancer progression or treatment through modifying autophagy.

In recent decades, inertial microfluidic devices have been widely used for cell separation. However, these techniques inevitably exert mechanical stresses, causing cell damage and death during the separation process. This remains a significant challenge for their biological and clinical applications. Despite extensive research on cell separation, the effects of mechanical stresses on cells in microfluidic separation have remained insufficiently explored. This review focuses on the effects of mechanical stresses on cells, particularly in spiral microchannels and contraction-expansion arrays (Contraction and Expansion Arrays (CEAs)). We derived the approximated magnitude of shear stress in a spiral microchannel, extensional stress in CEAs and conventional methods, along with exposure time in a single map to illustrate cell damage and operational zones. Finally, this review serves as a practical guideline to help readers in evaluating stress damages, enabling the effective selection of appropriate techniques that optimize cell viability and separation efficiency for biological and clinical applications.

Chinese hamster ovary (CHO) cells are commonly used to produce recombinant therapeutic proteins (RTPs). While recent strategies have significantly improved the expression levels of RTPs in CHO cells, insufficient secretion and endoplasmic reticulum (ER) stress remain major bottlenecks. Therefore, further understanding of the mechanism of the ER stress response, optimization of ER-related folding and degradation pathways, and development of more efficient ER engineering tools are expected to overcome this issue and maximize RTP production. In this review, we summarize the role of ER in recombinant proteins production and explore ER engineering strategies to improve the yield of recombinant proteins in CHO cells. We further discuss ER-related strategies that can improve recombinant protein production, future research directions, and prospective applications.

Excessive reactive oxygen species (ROS) levels cause oxidative stress, which can lead to various diseases. Renal failure is associated with oxidative stress and mitochondrial dysfunction. Vitamin K1 (phylloquinone) and K2 (menaquinone) are essential for blood coagulation and bone formation. Vitamin K has been shown to have anti-inflammation, glucose metabolism regulation, and antiferroptosis functions. We investigated the impact of menaquinone-4 (MK-4) on oxidative stress and mitochondrial dysfunction in human renal proximal tubular cells. MK-4 protected cells from oxidative damage induced by l-buthionine-(S,R)-sulfoximine (BSO), a selective inhibitor of glutathione metabolism, by inhibiting cell death, mitochondrial ROS production, and lipid peroxidation. MK-4 also reduced lactate production, prevented mitochondrial fragmentation, and improved mitochondrial respiratory function, indicating cytoprotective effects. Moreover, it enhanced intracellular ATP production and respiratory capacity, even in the absence of oxidative stress. Thus, MK-4 plays an important role in mitochondrial function in renal proximal tubular cells.

Alzheimer's disease (AD) is a well-established neurodegenerative disorder characterized by memory impairment, cognitive dysfunction, and behavioral disturbances. With the global population aging, the prevalence of AD continues to rise, presenting significant challenges to both society and healthcare systems. Curcumin, a polyphenolic compound derived from turmeric rhizomes, has demonstrated considerable potential in AD treatment due to its anti-inflammatory, antioxidant, and neuroprotective properties. However, its clinical application remains constrained by chemical instability, poor water solubility, rapid metabolism, and accelerated elimination. To overcome these limitations, various curcumin derivatives have been synthesized, and combination therapy strategies have been explored. This review examines the potential mechanisms through which curcumin may exert therapeutic effects in AD, including the inhibition of neuroinflammation, regulation of tau protein hyperphosphorylation, modulation of amyloid-β peptides, and provision of antioxidant benefits. Additionally, the advantages of curcumin derivatives and combination therapy approaches are discussed, offering novel perspectives and promising strategies for AD treatment. It is anticipated that advancements in drug design and therapeutic approaches will contribute to the development of more effective treatment options for AD.

Autophagy is an important factor in temozolomide (TMZ) resistance in glioblastoma (GBM). Receptor-interacting protein 2 (RIP2) is associated with autophagy, but its role and mechanism in regulating autophagy in GBM cells remain unclear. To analyze RIP2 expression in GBM in The Cancer Genome Atlas (TCGA) dataset. GBM cells were stimulated using recombinant human RIP2 protein (rRIP2) or RIP2 plasmid. Cell proliferation and apoptosis were assessed using CCK-8 assay and flow cytometry. Western blotting and immunofluorescence (IF) assays were performed to detect protein expression in cells and tumor tissues. Moreover, the relationship between RIP2-induced autophagy and TMZ resistance was verified in a GBM xenograft model. We determined that RIP2 expression was upregulated in GBM. rRIP2 and RIP2 overexpression induced TMZ resistance in the GBM cell lines. RIP2 overexpressing xenograft tumors have reduced sensitivity to TMZ. In addition, we showed that PD-L1 protein expression was upregulated in GBM tissues with RIP2 overexpression. rRIP2 and RIP2 overexpression induced autophagy in GBM cells through AMPK. Notably, RIP2 upregulated PD-L1 expression through the NF-κB signaling pathway, which induced autophagy and TMZ resistance in GBM cells. Moreover, NF-κB or autophagy inhibition reversed TMZ resistance in RIP2 overexpressing GBM cells in a xenograft model. In conclusion, RIP2 induces TMZ resistance in GBM cells by promoting autophagy through the NF-κB/PD-L1 signaling pathway, indicating that the RIP2/NF-κB/PD-L1 pathway may be therapeutic target for TMZ resistance.

Motor neuron diseases (MNDs) are a heterogeneous group of neurodegenerative disorders characterized by the progressive loss of motor neurons, resulting in debilitating physical decline. Advances in genetics have revolutionized the understanding of MNDs, elucidating critical genes such as SOD1, TARDBP, FUS, and C9orf72, which are implicated in their pathogenesis. Despite these breakthroughs, significant gaps persist in understanding the interplay between genetic and environmental factors, the role of rare variants, and epigenetic contributions. This review synthesizes current knowledge on the genetic landscape of MNDs, highlights challenges in linking genotype to phenotype, and discusses the promise of precision medicine approaches. Emphasis is placed on emerging strategies, such as gene therapy and targeted molecular interventions, offering hope for personalized treatments. Addressing these challenges is imperative to harness the full potential of genomics for improving outcomes in MNDs.

Cell death occurs continuously throughout individual development. By removing damaged or senescent cells, cell death not only facilitates morphogenesis during the developmental process, but also contributes to maintaining homeostasis after birth. In addition, cell death reduces the spread of pathogens by eliminating infected cells. Cell death is categorized into two main forms: necrosis and programmed cell death. Programmed cell death encompasses several types, including autophagy, pyroptosis, apoptosis, necroptosis, ferroptosis, and PANoptosis. Autophagy, a mechanism of cell death that maintains cellular equilibrium via the breakdown and reutilization of proteins and organelles, is implicated in regulating almost all forms of cell death in pathological contexts. Notably, necroptosis, ferroptosis, and PANoptosis are directly classified as autophagy-mediated cell death. Therefore, regulating autophagy presents a therapeutic approach for treating diseases such as inflammation and tumors that arise from abnormalities in other forms of programmed cell death. This review focuses on the crosstalk between autophagy and other programmed cell death modalities, providing new perspectives for clinical interventions in inflammatory and neoplastic diseases.

Intermittent fasting (IF) is a dietary approach that influences key metabolic pathways, including autophagy-a crucial mechanism in maintaining cellular homeostasis. Autophagy plays a dual role in oncogenesis, acting both as a tumor suppressor and a survival mechanism under metabolic stress. IF has shown potential for reducing cancer risk and enhancing therapeutic efficacy by sensitizing tumor cells to chemotherapy and radiotherapy. However, its effects depend heavily on the type and stage of cancer. Potential risks, such as excessive weight loss and malnutrition, require careful evaluation. Further clinical studies are needed to optimize IF protocols as adjuncts to cancer therapy. This review discusses autophagy mechanisms induced by IF, their therapeutic implications in oncology, and the limitations of this dietary strategy.

Autophagy is a "self-eating" biological process that degrades cytoplasmic contents to ensure cellular homeostasis. Its response to stimuli occurs in two stages: Within a few to several hours of exposure to a stress condition, autophagic flow rapidly increases, which is mediated by post-translational modification (PTM). Subsequently, the transcriptional program is activated and mediates the persistent autophagic response. O-linked β-N-acetylglucosamine (O-GlcNAc) modification is an inducible and dynamically cycling PTM; mounting evidence suggests that O-GlcNAc modification participates in the total autophagic process, including autophagy initiation, autophagosome formation, autophagosome-lysosome fusion, and transcriptional process. In this review, we summarize the current knowledge on the emerging role of O-GlcNAc modification in regulating autophagy-associated proteins and explain the different regulatory effects on autophagy exerted by O-GlcNAc modification.

Morphine has been a widely used drug for pain management and anesthesia in clinical settings for centuries and is also a drug of abuse. Its illicit use by individuals with substance use disorders has resulted in numerous brain-related complications. The immunopharmacology of morphine is highly complex, necessitating a deeper understanding of its interactions with brain regions involved in learning and memory. Autophagy is a conserved physiological recycling process that degrades cytoplasmic organelles and proteins, repurposing their components for cellular function. However, recent studies indicate that morphine exposure disrupts autophagic processes, contributing to many morphine-associated complications. This article highlights recent advancements in understanding the interplay between morphine and autophagy. By exploring this intricate relationship, we aim to enhance our knowledge of morphine-associated complications and autophagy dysregulation, potentially improving the management of morphine use disorder and related conditions, thereby promoting healthier outcomes.

Glaesserella parasuis (Gps) is an important pathogen that causes polyserositis, peritonitis and meningitis in pigs, causing considerable economic losses to the pig industry worldwide. In recent years, due to the abuse of antibiotic drugs, Gps drug resistance and multi-drug resistance have become increasingly serious, especially for macrolides. Thus, by inducing Tydigrosin resistant bacteria, we found that PgtP is a Gps-produced virulence gene that plays a crucial role in the disease, but its interaction in host cells remains unclear. To characterize the function of the PgtP gene in Gps, we constructed ΔPgtP mutants. Notably, deletion of the PgtP gene resulted in increased adhesion to mouse macrophages, suggesting that PgtP is essential for adhesion of Gps. In addition, as a member of the cell membrane transporter family, PgtP links activated inflammation with autophagy and oxidative stress metabolism. To further investigate the role of PgtP, we infected mouse macrophages with ΔPgtP mutants and wild strains respectively. We found that ΔPgtP mutations can reduce the level of intracellular reactive oxygen species (ROS), up-regulate the number of intracellular autophagosomes, and down-regulate the expression of cytokines IL-6 and TNF-a. Further mechanistic studies showed that PGTP-associated p38 mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways were involved in autophagy and oxidative stress and demonstrated that the related signaling pathways were also activated in mice. These results highlight the potential of PgtP as a target for therapeutic intervention and provide important new insights into how it contributes to the aggressiveness and persistence of Gps.

Muscle is one of the most abundant tissues in the human body, and its aging usually leads to many adverse consequences. Zebrafish is a powerful model used to study human muscle diseases, yet we know little about the molecular mechanisms of muscle aging in zebrafish. In this study, we determined the gene expression profiles of muscle tissues from male zebrafish of four different ages. Through differential expression analysis and expression pattern analysis, we identified a set of genes associated with muscle aging in zebrafish. Functional enrichment analysis revealed that several biological changes accompanied zebrafish muscle aging, including chronic inflammation, accumulation of sphingolipids, reduction of autophagy, and activation of the ferroptosis pathway. H&E staining showed that zebrafish muscle senescence leads to myofibrillar interstitial expansion and inflammatory cell infiltration. Furthermore, we screened zebrafish muscle aging related biomarkers by machine learning and verified the expression levels of some biomarkers by RT-qPCR. Based on these biomarkers, we constructed a zebrafish muscle aging clock that can predict muscle age based on transcriptomic data. This study provides us with a new perspective to understand the molecular mechanism of muscle aging and a new tool for zebrafish-based anti-aging research.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by a high recurrence rate and a lack of effective targeted therapies. The purpose of this study was to investigate the interaction between the pro-apoptotic factor phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1) and autophagy-related protein 5 (ATG5), as well as their regulatory mechanisms in TNBC cell apoptosis and autophagy, to identify potential therapeutic targets for TNBC.

TNBC-related datasets were retrieved from The Cancer Genome Atlas and selected by Prediction Analysis of Microarray 50 analysis to assess the expression of PMAIP1 in the samples. Additionally, the expression of PMAIP1 in the TNBC cell lines (MDA-MB-231) was detected using quantitative real-time polymerase chain reaction. In MDA-MB-231 cells, the expression of PMAIP1 and ATG5 was overexpressed or knocked down, and autophagy was inhibited using chloroquine (20 μM). Gene and protein expression levels were evaluated using quantitative real-time polymerase chain reaction and Western blot, respectively. Immunofluorescence was used to observe microtubule-associated protein 1 light chain 3 puncta formation to assess autophagy levels. Furthermore, cell apoptosis, proliferation, migration, and invasion were analyzed using terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, colony formation assay, and Transwell assay.

Compared to the control group, the expression of PMAIP1 was significantly elevated in TNBC tissues and MDA-MB-231 cells. Furthermore, overexpression of PMAIP1 led to a marked increase in apoptosis levels and a remarkable reduction in autophagy levels in MDA-MB-231 cells, while knockdown of PMAIP1 showed the opposite effects. Additionally, knockdown of ATG5 expression or treatment with chloroquine not only resulted in an increase in PMAIP1 expression in a time-dependent manner, but also reduced autophagy levels and enhanced apoptosis levels of cells. Furthermore, simultaneous knockdown of PMAIP1 and ATG5 considerably up-regulated apoptosis levels while down-regulating autophagy levels. Moreover, knockdown of PMAIP1 alone promoted the viability, invasion, and migration abilities of TNBC cells, while dual knockdown reversed these effects.

Inhibition of ATG5-mediated autophagy maintains PMAIP1 stability, thereby promoting cell apoptosis and suppressing TNBC progression.

Age-related retinopathy is one of the leading causes of visual impairment and irreversible blindness, characterized by progressive neuronal and myelin loss. The damages caused by oxidation contributes to the hallmarks of aging and represents fundamental components in pathological pathways that are thought to drive multiple age-related retinopathies. Quercetin (Que), a natural polyphenol abundant in vegetables, herbs, and fruits, has been extensively studied for its long-term antioxidative effects mediated through diverse mechanisms. Additionally, Que and its derivatives exhibit a broad spectrum of pharmacological characteristics in the cellular responses of age-related retinopathy induced by oxidative stress, including anti-inflammatory, anti-neovascularization, regulatory, and neuroprotective effects in autophagy and apoptosis processes. This review mainly focuses on the antioxidative mechanisms and curative effects of Que treatment for various age-related retinopathies, such as retinitis pigmentosa, diabetic retinopathy, age-related macular degeneration, and glaucoma. Furthermore, we discuss emerging technologies and methods involving Que and its derivatives in the therapeutic strategies for age-related retinopathies, highlighting their promise for clinical translation.

Acute lung injury (ALI), including its most severe form, acute respiratory distress syndrome (ARDS), is a common cause of acute hypoxemic respiratory failure. Although its clinical characteristics have been well characterized, the relevant mechanism remains unclear. An imbalance in autophagy leads to alveolar remodeling and triggers the pathogenesis of ARDS. In this study, we assessed the therapeutic efficacy of the STAT1 inhibitor fludarabine (Fluda) in ALI. C57BL6 mice were exposed to lipopolysaccharide (LPS), and their lung tissues were analyzed via next-generation transcriptome sequencing.

Western blotting revealed that interferon regulatory factor 1 (IRF1) was highly expressed and STAT1 was phosphorylated following LPS exposure. Fluda significantly decreased the protein expression of STAT1/IRF1 and inhibited the alveolar infiltration of neutrophils and macrophages. Nitric oxide (NO), inducible nitric oxide synthase, tumor necrosis factor-α (TNF-α), interferon-γ, and interleukin-6 (IL-6) release was decreased in the lungs of mice and RAW264.7 macrophages following Fluda treatment. In LPS-induced GFP-LC3 transgenic mice treated with Fluda, the counts of LC3-expressing neutrophils and macrophages in bronchoalveolar (BAL) fluid were significantly decreased. Furthermore, Fluda decreased LC3 and p62 protein expression, thereby inhibiting the release of NO, IL-6, and TNF-α in BAL. In RAW264.7 cells, the inhibition of STAT1/IRF1 by Fluda decreased LPS-induced ERK and NF-κB p65 phosphorylation.

The inhibition of STAT1/IRF1 by Fluda plays a pivotal role in modulating dysregulated autophagy by suppressing the MAPK and NF-κB p65 pathways in ALI.

In this work, we have carefully designed and synthesized two Ru(II) metal complexes: [Ru(phen)2(HMPIP)](PF6)2 (6a, where phen = 1,10-phenanthroline, HMPIP = 2-(2-hydroxy-3-methylphenyl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ru(bpy)2(HMPIP)](PF6)2 (6b, where bpy = 2,2'-bipyridine). Using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to explore the cytotoxicity of 6a and 6b towards HepG2, B16, A549, SGC-7901, HCT116 and non-cancer LO2. The complexes exhibited cytotoxicity activity against HepG2 cells. The capacity of 6a and 6b to impede the proliferation and dissemination of cancer cells was evaluated by conducting proliferation and migration experiments and 3D model. The anticancer mechanism was investigated in detail. The utilization of cycle blocking assays revealed that 6a and 6b induced a G0/G1 phase arrest in HepG2 cells. The cellular uptake experiments show that the complexes enter the cell nuclei, then escape from the cell nuclei into the cytoplasm, finally accumulate in the mitochondria. Apoptosis assays and the examination of proteins indicated that the complexes were capable of efficiently inducing apoptosis in HepG2 cells. Additionally, the potential induction of autophagy-mediated cell death was explored. The observed reduction in glutathione (GSH) levels and glutathione peroxidase 4 (GPX4) expression suggested a disruption of redox homeostasis within cancer cells, an increment in malondialdehyde (MDA) amount, together with BODIPY staining experiment, confirm that 6a and 6b can induce ferroptosis. Interestingly, in a nude mouse model, 6a showed a significant suppression of tumor growth with an inhibition rate of 63.4 %, without causing any weight loss of mice. The studies on the mechanism show that 6a causes immune cell death, increase the amount of TNF-α and IFN-γ, reduce IL-10 content, which further activates immune response to increase CD8+ T cells to prevent tumor growth. Therefore, 6a inhibits the tumor growth through stimulating the immune response to increase CD8+ T cells. In addition, the experiments in vitro show that the complexes through inhibition of PI3K/AKT/mTOR signaling pathway and intrinsic mitochondria pathway to cause cell apoptosis. These results demonstrate that Ru(II) complexes may be potent anticancer candidates for HepG2 tumor.

Palmitic acid (PA), being the most prevalent free fatty acid in the human, holds significant implications as a risk factor for atherosclerosis (AS) due to its ability to induce physiological dysfunction in endothelial cells (ECs). Endothelial cell-specific molecule 1 (ESM1), has been identified as a marker for activated ECs. Nevertheless, the mechanisms underlying ESM1-induced endothelial cell proliferation remain elusive. The expression of ESM1, ANGPTL4 and autophagy related protein were confirmed by western blot. Proliferation ability was tested by MTT and EdU. Lipids level was confirmed by Oil red staining. Autophagic flux was confirmed by Monodansylcadaverine (MDC) staining and pCMV-mCherry-GFP-LC3B fluorescence staining assay. The mouse model of AS was used to observe the effect of PA on the ESM1-ANGPTL4-autophagy signaling axis. This study elucidates ESM1-ANGPTL4 axis in maintaining proliferation of ECs and lipid reprogramming. Furthermore, it has been observed that PA has the ability to stimulate EC to autonomously increase the expression of ESM1, which in turn can counteract the detrimental effects of PA on ECs. Conversely, when ESM1 is suppressed, the damaging effects of PA on ECs are exacerbated. Mechanistically, our findings indicate that ESM1 facilitates EC proliferation and lipids homeostasis by up-regulating autophagy through ANGPTL4. This effect of ESM1 on ECs can be attenuated by ATG7 inhibiting. Additionally, the serum levels of ESM1 were found to be elevated in AS mice. ESM1 was found to enhance ECs proliferation and mitigate endothelial cell injury induced by PA through the upregulation of autophagy. This mechanism potentially serves as a protective factor against atherosclerosis progression.

Cardiovascular diseases (CVDs) remain a global health challenge, with programmed cell death (PCD) mechanisms like apoptosis and necroptosis playing key roles in the progression. Circular RNAs (circRNAs) have recently been recognized as crucial regulators of gene expression, especially in modulating PCD. In current researches, circRNA regulation of apoptosis is the most studied area, followed by autophagy and ferroptosis. Notably, the regulatory role of circRNAs in pyroptosis and necroptosis has also begun to attract attention. From a mechanistic perspective, circRNAs influence cellular processes through several modes of action, including miRNA sponging, protein interactions, and polypeptide translation. Manipulating circRNAs and their downstream targets through inhibition or overexpression offers versatile therapeutic options for CVD treatment. Continued investigation into circRNA-mediated mechanisms may enhance our understanding of CVD pathophysiology and underscore their potential as novel and promising therapeutic targets.

Autophagy is a cytoprotective process that operates within a cell to maintain cellular homeostasis. An array of multiple proteins is involved to mediate this conserved cellular process. Among these, Beclin 1 protein encoded by BECN1 gene plays a crucial role during the initiation of autophagy. It acts as a molecular platform onto which multiple proteins interact to mediate autophagy initiation. The functioning of such proteins has reportedly been influenced by the molecular markers such as Single Nucleotide Polymorphisms (SNPs) present within the encoding gene. The SNPs within the autophagy gene have been known to influence the functioning of autophagy proteins which further is involved in various diseases. Studies have reported that the SNPs within the BECN1 are involved in various diseases. This report outlines the findings of all the existing research on the role of SNPs within BECN1.

This study aims to investigate the expression and possible role of autophagy in the retina of rats under microgravity.

Adult Sprague-Dawley (SD) rats were randomly allocated to either the tail suspension group (TS) or the control group (CTRL). To simulate microgravity-induced redistribution of cephalad fluid observed in space, the rats in the TS group underwent tail suspension for a duration of 4 weeks. Optical coherence tomography angiography (OCTA) was applied to assess the ocular blood flow and thickness of the retina. Hematoxylin and eosin (H&E) staining, along with transmission electron microscopy (TEM), were used to investigate morphological changes and autophagosomes in the retina. Endoplasmic reticulum autophagy (ER-phagy) related proteins (ATF4, CHOP, and GRP78) in the rat retina were detected using an immunofluorescence assay (IFA). The levels of autophagy-related proteins (Beclin1, P62, LC3B, ATF4, CHOP, and GRP78) were quantified by Western blot (WB). The expression of ATG5 and ATG7 genes was examined via real-time quantitative PCR (qPCR).

In fundus imaging signs, microgravity increases retinal thickness and the retinal vascular perfusion area. Moreover, microgravity also upregulates Beclin1, LC3B, ATF4, CHOP, and GRP78 while downregulating P62 in retina. It elevates the number of autophagosomes and activates autophagy and ER-phagy signaling pathways in retina.

Simulated microgravity can trigger the organism's intrinsic protective mechanisms, inducing the activation of autophagy (ER-phagy) in the retina, which may represent a self-defense mechanism against adverse conditions of microgravity-related stressors.

Cervical cancer (CC) is a prevalent malignancy among women with high morbidity and poor prognosis. Sorting nexin 10 (SNX10) is a newly recognized cancer regulatory factor, while its action on CC progression remains elusive. Hence, this study studied the effect of SNX10 on CC development and investigated the mechanism.

The SNX10 level in CC and the overall survival of CC cases with different SNX10 expressions were determined by bioinformatics analysis in GEPIA. The SNX10 expression in tumor tissues and clinical significance were studied in 64 CC cases. The overall survival was assessed using Kaplan-Meier analysis. The formation of LC3 was evaluated using immunofluorescence. Cell invasion was measured using the Transwell assay. Epithelial-to-mesenchymal transition (EMT) was determined by observing cell morphology and assessing EMT marker levels. A xenograft tumor was constructed to evaluate tumor growth.

SNX10 was elevated in CC tissues and cells, and the CC cases with high SNX10 levels exhibited poor overall survival. Besides, SNX10 correlated with the FIGO stage, lymph node invasion, and stromal invasion of CC. SNX10 silencing induced CC cell autophagy and suppressed CC cell invasion and EMT. Meanwhile, silenced SNX10 could suppress invasion and EMT via inducing autophagy. Furthermore, SNX10 inhibition suppressed the PI3K/AKT pathway. Moreover, silenced SNX10 restrained the tumor growth, autophagy, and EMT of CC in vivo.

SNX10 was enhanced in CC and correlated with poor prognosis. Silenced SNX10 induced autophagy to suppress invasion and EMT and inhibited the PI3K/AKT pathway in CC, making SNX10 a valuable molecule for CC therapy.

Endocrine-disrupting chemicals (EDCs) significantly contribute to health issues by interfering with hormonal functions. Bisphenol A (BPA), a prominent EDC, is extensively utilized as a monomer and plasticizer in producing polycarbonate plastic and epoxy resins, making it one of the highest-demanded chemicals in commercial use. This is the major component used in plastic products, including bottles, containers, storage items, and food serving ware. Exposure of BPA happens through oral, respiratory, transdermal routes and eye contact. As an EDC, BPA disrupts hormonal binding, leading to various health problems, such as cancers, reproductive abnormalities, metabolic syndrome, immune dysfunction, neurological effects, cardiovascular problems, respiratory issues, and obesity. BPA mimics the hormone estrogen but exhibits a weak affinity for estrogen receptors. This weak binding affinity triggers multiple cell death pathways, including necroptosis, pyroptosis, apoptosis, ferroptosis, and autophagy, across different cell types. Numerous clinical, in-vitro, and in-vivo experiments have demonstrated that BPA exposure results in unfavorable health effects. This review highlights the mechanisms of cell death pathways initiated through BPA exposure and the associated negative health consequences. The extensive use of BPA and its frequent detection in environmental and biological models underscore the urgent need for further investigation into its effects and the development of safe alternatives. Addressing the health risks posed by BPA involves a comprehensive approach that includes reducing exposure and finding novel substitutes to lessen its detrimental impact on humans.

Immune checkpoint inhibitors, especially those targeting CD274/PD-L1yield powerful clinical therapeutic efficacy. Thoughmuch progress has been made in the development of antibody-basedCD274 drugs, chemical compounds applied for CD274degradation remain largely unavailable. Herein,baicalein, a monomer of traditional Chinese medicine, isscreened and validated to target CD274 and induces itsmacroautophagic/autophagic degradation. Moreover, we demonstrate thatCD274 directly interacts with MAP1LC3B (microtubule associatedprotein 1 light chain 3 beta). Intriguingly, baicalein potentiatesCD274-LC3 interaction to facilitate autophagic-lysosomal degradationof CD274. Importantly, targeted CD274. degradation via baicaleininhibits tumor development by boosting T-cell-mediated antitumorimmunity. Thus, we elucidate a critical role of autophagy-lysosomalpathway in mediating CD274 degradation, and conceptually demonstratethat the design of a molecular "glue" that tethers the CD274-LC3interaction is an appealing strategy to develop CD274 inhibitors incancer therapy.Abbreviations: ATTECs: autophagy-tethering compounds; AUTACs: AUtophagy-TArgeting Chimeras; AUTOTACs: AUTOphagy-TArgeting Chimeras; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; BiFC: bimolecular fluorescence complementation; BafA1: bafilomycin A1; CD274/PD-L1/B7-H1: CD274 molecule; CQ: chloroquine; CGAS: cyclic GMP-AMP synthase; DAPI: 4'6-diamino-2-phenylindole; FITC: fluorescein isothiocyanate isomer; GFP: green fluorescent protein; GZMB: granzyme B; IHC: immunohistochemistry; ICB: immune checkpoint blockade; KO: knockout; KD: equilibrium dissociation constant; LYTAC: LYsosome-TArgeting Chimera; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MST: microscale thermophoresis; NFAT: nuclear factor of activated T cells; NFKB/NF-kB: nuclear factor kappa B; NSCLC: non-small-cell lung cancer; PDCD1: programmed cell death 1; PROTACs: PROteolysis TArgeting Chimeras; PRF1: perforin 1; PE: phosphatidylethanolamine; PHA: phytohemagglutinin; PMA: phorbol 12-myristate 13-acetate; STAT: signal transducer and activator of transcription; SPR: surface plasmon resonance; TILs: tumor-infiltrating lymphocyte; TME: tumor microenvironment.

Prostaglandin G/H synthase 1 (PTGS1) is known to regulate platelet function and inflammation. However, its role in atrial fibrillation (AF)-related thrombosis is not well understood. This study investigates the role of PTGS1 in AF-associated thrombus formation and its underlying mechanisms.

Left atrial appendage (LAA) tissues were collected from 48 patients undergoing valve replacement surgery, divided into three groups: sinus rhythm (SR), AF with thrombus [AF (+) T (+)], and AF without thrombus [AF (+) T (-)]. PTGS1 expression, platelet activation markers (MPA, sCD40L, and d-dimer), macrophage phenotypes (M1 and M2), inflammatory cytokines (IL-1β, TNF-α, IL-6), and autophagy-related proteins (LC3II and p62) were assessed. Furthermore, the effect of PTGS1 manipulation on autophagy in endocardial endothelial cells (EECs) was examined using cell transfection experiments.

PTGS1 expression was significantly higher in LAA tissues of AF (+) T (+) patients compared to AF (+) T (-) and SR groups. It was positively correlated with reduced LAA emptying velocity (LAAEV), higher CHA2DS2-VASc scores, and elevated platelet activation markers (MPA, sCD40L, and d-dimer). Data also showed increased M1 macrophage infiltration and higher pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) in AF (+) T (+) patients, with PTGS1 expression strongly linked to these markers. Furthermore, PTGS1 overexpression inhibited autophagy in EECs by decreasing LC3II/LC3I ratio and increasing p62 levels, while PTGS1 knockdown promoted autophagy, protecting against endothelial dysfunction.

PTGS1 is overexpressed in AF patients with thrombosis and may play an important role in promoting thrombus formation through enhanced platelet activation, inflammation, and inhibition of autophagy.

Cells may be intrinsically fated to die to sculpt tissues during development or to maintain homeostasis. Cells can also die in response to various stressors, injury or pathological conditions. Additionally, cells of the metazoan body are often highly specialized with distinct domains that differ both structurally and with respect to their neighbors. Specialized cells can also die, as in normal brain development or pathological states and their different regions may be eliminated via different programs. Clearance of different types of cell debris must be performed quickly and efficiently to prevent autoimmunity and secondary necrosis of neighboring cells. Moreover, all cells, including those programmed to die, may be subject to various stressors. Some largely unexplored questions include whether predestined cell elimination during development could be altered by stress, if adaptive stress responses exist and if polarized cells may need compartment-specific stress-adaptive programs. We leveraged Compartmentalized Cell Elimination (CCE) in the nematode C. elegans to explore these questions. CCE is a developmental cell death program whereby three segments of two embryonic polarized cell types are eliminated differently. We have previously employed this in vivo genetic system to uncover a cell compartment-specific, cell non-autonomous clearance function of the fusogen EFF-1 in phagosome closure during corpse internalization. Here, we introduce an adaptive response that serves to aid developmental phagocytosis as a part of CCE during stress. We employ a combination of forward and reverse genetics, CRISPR/Cas9 gene editing, stress response assays and advanced fluorescence microscopy. Specifically, we report that, under heat stress, the selective autophagy receptor SQST-1/p62 promotes the nuclear translocation of the oxidative stress-related transcription factor SKN-1/Nrf via negative regulation of WDR-23. This in turn allows SKN-1/Nrf to transcribe lyst-1/LYST (lysosomal trafficking associated gene) which subsequently promotes the phagocytic resolution of the developmentally-killed internalized cell even under stress conditions.

Maintaining proteostasis is critical for neuronal health, with its disruption underpinning the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. Nuclear Factor Erythroid 2-Related Factor 1 (NFE2L1) has emerged as a key regulator of proteostasis, integrating proteasome function, autophagy, and ferroptosis to counteract oxidative stress and protein misfolding. This review synthesizes current knowledge on the role of NFE2L1 in maintaining neuronal homeostasis, focusing on its mechanisms for mitigating proteotoxic stress and supporting cellular health, offering protection against neurodegeneration. Furthermore, we discuss the pathological implications of NFE2L1 dysfunction and explore its potential as a therapeutic target. By highlighting gaps in the current understanding and presenting future research directions, this review aims to elucidate NFE2L1's role in advancing treatment strategies for neurodegenerative diseases.

Non-alcoholic fatty liver disease (NAFLD) is one of the serious global health concerns, leading to non-alcoholic steatohepatitis (NASH), and to hepatocellular carcinoma (HCC). Despite its prevalence, the molecular mechanisms regulating NAFLD progression remain elusive. The present study aims to determine role of microRNA-122-mediated regulation of pyruvate kinase M2 (PKM2) on regulating inflammatory and autophagic proteins during the pathogenesis of NAFLD. Huh7 cells were incubated with free fatty acids (FFAs) or transfected with single guide RNA to PKM2 containing CRISPR-Cas9 system or miR-122 for up to 72 h. C57BL/6 mice were fed with sham-operated control, choline sufficient L-amino acid defined (CSAA) or choline-deficient L-amino acid defined (CDAA) diet for 6, 18, 32 and 54 weeks. The RNA or protein was isolated from the Huh7 cells and the liver tissue of the mice. RT-PCR was performed for miR-122 expression and Western blots were performed for PKM2, iNOS, COX2, Beclin-1, Atg7 and LC3-II. FFAs induced the expression of PKM2, iNOS and COX2, while decreased the expression of miR-122, Beclin-1, Atg7 and LC3-II. Overexpression of miR-122 resulted in decreased PKM2, iNOS and COX2 and increased Beclin-1, Atg7 and LC3-II. Silencing of PKM2 led to decreased iNOS and COX2 and increased Beclin-1, Atg7 and LC3-II. In CDAA fed-mice, there was a significant increase in PKM2, iNOS and COX2 and decreased miR-122, Beclin-1, Atg7 and LC3-II. The data showed that FFAs downregulated miR-122 expression, which resulted in the upregulation of PKM2, which in turn upregulated inflammatory proteins and downregulated autophagic proteins during the pathogenesis of NAFLD.