Asthma, a prevalent chronic disease, poses significant health threats and burdens healthcare systems. This study focused on the role of bronchial epithelial cells in asthma pathophysiology.

Bioinformatics was used to identify key asthmarelated genes. An ovalbumin-sensitized mouse model and an IL-13-stimulated Beas-2B cell model were established for further investigation.

Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) was identified as a crucial gene in asthma. CEACAM5 expression was elevated in asthmatic mouse lung tissues and IL-13-stimulated Beas-2B cells, primarily in bronchial epithelial cells. CEACAM5 induced reactive oxygen species (ROS), lipid peroxidation, and ferroptosis. Interfering with CEACAM5 reduced ROS, malondialdehyde levels, and enhanced antioxidant capacity, while inhibiting iron accumulation and autophagy. Overexpression of CEACAM5 in IL-13-stimulated cells activated the JAK/STAT6 pathway, which was necessary for CEACAM5-induced autophagy, ROS accumulation, lipid peroxidation, and ferroptosis.

CEACAM5 promotes ferroptosis and autophagy in airway epithelial cells via the JAK/STAT6 pathway, exacerbating asthma symptoms. It represents a potential target for clinical treatment.

Acute central nervous system injuries, including ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, and spinal cord injury, are a major global health challenge. Identifying optimal therapies and improving the long-term neurological functions of patients with acute central nervous system injuries are urgent priorities. Mitochondria are susceptible to damage after acute central nervous system injury, and this leads to the release of toxic levels of reactive oxygen species, which induce cell death. Mitophagy, a selective form of autophagy, is crucial in eliminating redundant or damaged mitochondria during these events. Recent evidence has highlighted the significant role of mitophagy in acute central nervous system injuries. In this review, we provide a comprehensive overview of the process, classification, and related mechanisms of mitophagy. We also highlight the recent developments in research into the role of mitophagy in various acute central nervous system injuries and drug therapies that regulate mitophagy. In the final section of this review, we emphasize the potential for treating these disorders by focusing on mitophagy and suggest future research paths in this area.

Precise tumor therapy is essential for improving treatment specificity, enhancing efficacy, and minimizing side effects. Targeting organelles is a key strategy for achieving this goal and is a frontier research area attracting a considerable amount of attention. The concept of organelle targeting has a significant effect on the structural design of the nanodrugs employed. Most notably, the intricate interactions among different organelles in a tumor cell essentially create a unified system. Unfortunately, this aspect might have been somewhat overlooked when existing organelle-targeting nanodrugs were designed. In this review, we underscore the synergistic relationship among the various organelles and advocate for a holistic view of organelle-targeting design. Through the integration of biology and material science, recent advancements in organelle targeting, escaping, and collaborating are consolidated to offer fresh perspectives for the development of antitumor nanomedicines.

The transmembrane autophagy protein ATG9 has multiple functions essential for autophagosome formation. Here, we uncovered a novel function of ATG-9 in regulating lysosome biogenesis and integrity in Caenorhabditis elegans. Through a genetic screen, we identified that mutations attenuating the lipid scrambling activity of ATG-9 suppress the autophagy defect in epg-5 mutants, in which non-degradative autolysosomes accumulate. The scramblase-attenuated ATG-9 mutants promote lysosome biogenesis and delivery of lysosome-localized hydrolases and also facilitate the maintenance of lysosome integrity. Through manipulation of phospholipid levels, we found that a reduction in phosphatidylethanolamine (PE) also suppresses the autophagy defects and lysosome damage associated with impaired lysosomal degradation. Our results reveal that modulation of phospholipid composition and distribution, e.g., by attenuating the scramblase activity of ATG-9 or reducing the PE level, regulates lysosome function and integrity.

The multi-step macroautophagy/autophagy process ends with the cargo-laden autophagosome fusing with the lysosome to deliver the materials to be degraded. The metazoan-specific autophagy factor EPG5 plays a crucial role in this step by enforcing fusion specificity and preventing mistargeting. How EPG5 exerts its critical function and how its deficiency leads to diverse phenotypes of the rare multi-system disorder Vici syndrome are not fully understood. Here, we report the first structure of human EPG5 (HsEPG5) determined by cryo-EM and AlphaFold2 modeling. Our structure revealed that HsEPG5 is constructed from helical bundles analogous to tethering factors in membrane trafficking pathways but contains a unique protruding thumb domain positioned adjacent to the atypical tandem LIR motifs involved in interaction with the GABARAP subfamily of Atg8-family proteins. Our NMR spectroscopic, molecular dynamics simulations and AlphaFold modeling studies showed that the HsEPG5 tandem LIR motifs only bind the canonical LIR docking site (LDS) on GABARAP without engaging in multivalent interaction. Our co-immunoprecipitation analysis further indicated that full-length HsEPG5-GABARAP interaction is mediated primarily by LIR1. Finally, our biochemical affinity isolation, X-ray crystallographic analysis, affinity measurement, and AlphaFold modeling demonstrated that this mode of binding is observed between Caenorhabditis elegans EPG-5 and its Atg8-family proteins LGG-1 and LGG-2. Collectively our work generated novel insights into the structural properties of EPG5 and how it potentially engages with the autophagosome to confer fusion specificity.ABBREVIATIONS: ATG: autophagy related; CSP: chemical shift perturbation; eGFP: enhanced green fluoresent protein; EM: electron microscopy; EPG5: ectopic P-granules 5 autophagy tethering factor; GST: glutathione S-transferase; HP: hydrophobic pocket; HSQC: heteronuclear single-quantum correlation; ITC: isothermal titration calorimetry; LDS: LC3 docking site; LIR: LC3-interacting region; MD: molecular dynamics; NMR: nuclear magnetic resonance; TEV: tobacco etch virus.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract, primarily driven by KIT or PDGFRA mutations. Programmed cell death (PCD), including apoptosis, autophagy, and ferroptosis, plays a crucial role in GIST pathogenesis, progression, and treatment response. Non-coding RNAs (ncRNAs) have emerged as key regulators of PCD pathways, influencing GIST proliferation, metastasis, and drug resistance, particularly in response to tyrosine kinase inhibitors (TKIs) such as imatinib. Apoptosis suppression is strongly associated with poor prognosis, while autophagy contributes to tumor dormancy and TKI resistance. Ferroptosis, a novel iron-dependent cell death pathway, represents a promising therapeutic target. Recent evidence suggests that ncRNAs modulate these PCD pathways through interactions with key molecular regulators such as miR-494, miR-30a, and lncRNAs, which affect signaling networks including PI3K/AKT, MAPK, and mTOR. Furthermore, ncRNAs have mediated secondary resistance to imatinib by promoting autophagic flux and altering ferroptosis sensitivity. Understanding the molecular interplay between ncRNAs and PCD in GIST provides novel insights into disease mechanisms and offers potential therapeutic strategies to overcome drug resistance. Targeting ncRNA-mediated regulation of apoptosis, autophagy, and ferroptosis may enhance treatment efficacy and improve patient outcomes. Future research should focus on elucidating the mechanistic roles of ncRNAs in PCD pathways to develop innovative diagnostic and therapeutic approaches for GIST.

Necrosis at the ischemic distal end of flap transplants increases patients' pain and economic burden. Reactive oxygen species (ROS) and mitochondrial damage are crucial in regulating parthanatos, but the mechanisms linking disrupted macroautophagic/autophagic flux to parthanatos in ischemic flaps remain unclear. The results of western blotting, immunofluorescence staining, and a proteomic analysis revealed that the autophagic protein SNAP29 was deficient in ischemic flaps, resulting in disrupted autophagic flux, increased ROS-induced parthanatos, and aggravated ischemic flap necrosis. The use of AAV vector to restore SNAP29 in vivo mitigated the disruption of autophagic flux and parthanatos. Additionally, quantification of the total m6A level and RIP-qPCR, MeRIP-qPCR, and RNA stability assessments were performed to determine differential Snap29 mRNA m6A methylation levels and mRNA stability in ischemic flaps. Various in vitro and in vivo tests were conducted to verify the ability of METTL3-mediated m6A methylation to promote SNAP29 depletion and disrupt autophagic flux. Finally, we concluded that restoring SNAP29 by inhibiting METTL3 and YTHDF2 reversed the "autophagy-mitochondrial crisis", defined for the first time as disrupted autophagic flux, mitochondrial damage, mitochondrial protein leakage, and the occurrence of parthanatos. The reversal of this crisis ultimately promoted the survival of ischemic flaps.Abbreviations: AAV = adeno-associated virus; ACTA2/α-SMA = actin alpha 2, smooth muscle, aorta; AIFM/AIF = apoptosis-inducing factor, mitochondrion-associated; ALKBH5 = alkB homolog, RNA demythelase; Baf A1 = bafilomycin A1; CQ = chloroquine; DHE = dihydroethidium; ECs = endothelial cells; F-CHP = 5-FAM-conjugated collagen-hybridizing peptide; GO = gene ontology; HUVECs = human umbilical vein endothelial cells; KEGG = Kyoto Encyclopedia of Genes and Genomes; LC-MS/MS = liquid chromatography-tandem mass spectrometry; LDBF = laser doppler blood flow; m6A = N6-methyladenosine; MAP1LC3/LC3 = microtubule-associated protein 1 light chain 3; MeRIP = methylated RNA immunoprecipitation; METTL3 = methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit; NAC = N-acetylcysteine; OGD = oxygen glucose deprivation; PAR = poly (ADP-ribose); PARP1 = poly (ADP-ribose) polymerase family, member 1; PECAM1/CD31 = platelet/endothelial cell adhesion molecule 1; ROS = reactive oxygen species; RT-qPCR = reverse transcription quantitative polymerase chain reaction; RIP = RNA immunoprecipitation; SNAP29 = synaptosomal-associated protein 29; SNARE = soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1 = sequestosome 1; SRAMP = sequence-based RNA adenosine methylation site predicting; STX17 = syntaxin 17; TMT = tandem mass tag; TUNEL = terminal deoxynucleotidyl transferase dUTP nick end labeling; VAMP8 = vesicle-associated membrane protein 8; WTAP = WT1 associating protein; YTHDF2 = YTH N6-methyladenosine RNA binding protein 2; 3' UTR = 3'-untranslated region.

The NLRP3 inflammasome is crucial for immune responses. However, its overactivation can lead to severe inflammatory diseases, underscoring its importance as a target for therapeutic intervention. Although numerous inhibitors targeting NLRP3 exist, regulating its degradation offers an alternative and promising strategy to suppress its activation. The degradation of NLRP3 is primarily mediated by the proteasomal and autophagic pathways. The review not only elaborates on the traditional concepts of ubiquitination and NLRP3 degradation but also investigates the important roles of indirect regulatory modifications, such as phosphorylation, acetylation, ubiquitin-like modifications, and palmitoylation-key post-translational modifications (PTMs) that influence NLRP3 degradation. Additionally, we also discuss the potential targets that may affect NLRP3 degradation during the proteasomal and autophagic pathways. By unraveling these complex regulatory mechanisms, the review aims to enhance the understanding of NLRP3 regulation and its implications for developing therapeutic strategies to combat inflammatory diseases.

Autophagy is a general eukaryotic mechanism for the degradation and recycling of macromolecules and organelles, whereby the ATG1-kinase complex plays a crucial initiator role. To understand the role of autophagy-related genes in the growth and development of the entomopathogenic parasitoid fungus Cordyceps militaris, we constructed ΔCmATG1 and ΔCmATG13 knockout strains. Compared with the wild type, both knockout strains exhibited severe defects in terms of hyphal morphology, fruiting body formation, conidial production and germination rates, pathogenicity, as well as growth rates under nutritional stress. Moreover, the content of cordycepin, ergosterol, and the levels of phospholipids all exhibited significant decreases, indicating that both ΔCmATG1 and ΔCmATG13 impaired autophagy in the respective knockout strains. Comparative transcriptomic analysis of the wild type and ΔCmATG1 revealed that differentially expressed genes were mainly enriched in phosphoglyceride metabolism, the MAPK signaling pathway, and autophagy-related processes. Taken together, these results demonstrate that the ATG1-kinase complex plays a crucial role in the development of fruiting bodies in C. militaris. This study lays a foundation for further analysis of the molecular mechanisms underlying the role of autophagy in the formation of macrofungal fruiting bodies.

Autophagy is a highly conserved metabolic process that regulates cellular homeostasis and energy supply by degrading dysfunctional and excess cell constituents and reserve materials into products that are reused in metabolic and biosynthetic pathways. Macroautophagy is the best studied form of autophagy in invertebrates. Starvation is a common stress factor triggering autophagy in overwintering animals. In arachnids, the midgut diverticula cells perform many vital metabolic functions and are therefore critically involved in the response to starvation. Here we studied macroautophagy in three species which apply different modes for overwintering in caves: the harvestmen Gyas annulatus in diapause, Amilenus aurantiacus with ongoing ontogenesis under fasting conditions, and the spider Meta menardi, which feeds opportunistically even in winter. The main goal was to find eventual qualitative and quantitative differences in autophagic processes by inspecting TEM micrographs. In all three species, the rates of midgut epithelial cells with autophagic structures gradually increased during overwintering, but were significantly lower in G. annulatus in the middle and at the end of overwintering than in the other two species, owing to metabolic activity having been more suppressed. Decomposition of mitochondria and glycogen took place in autophagic structures in all three species. Moreover, spherite disintegration in A. aurantiacus and a special form of lipid disintegration through "lipid bubbly structures" in M. menardi indicate the crucial involvment of selective autophagy, while no specific autophagy was observed in G. annulatus. We conclude that autophagic activities support overwintering in different ways in the species studied.

TNF receptor-associated factor 3 interacting protein 3 (TRAF3IP3/T3JAM) exhibits dual roles in cancer progression. While upregulated in most malignancies and critical for immune regulation. However, the specific effects and molecular mechanisms of TRAF3IP3 on the progression of lung adenocarcinoma (LUAD) remains poorly understood. This study reveals TRAF3IP3 is upregulated in several tumor tissues but exclusively decreased in LUAD and Lung squamous cell carcinoma (LUSC) tissues, consequential in a favorable overall survival (OS) in LUAD rather than LUSC. Herein, it is reported that TRAF3IP3 can suppress cell proliferation and promote the apoptosis rate of LUAD cells by inducing excessive ER stress-related apoptosis. Importantly, TRAF3IP3 triggers ER stress via the PERK/ATF4/CHOP pathway, accompanied by stimulated ER stress-induced cytoprotective autophagy in LUAD cells. Through IP-MS analysis, STRN3 is identified as a direct downstream interactor with TRAF3IP3 and corroborated to regulate ER stress positively. Mechanistically, TRAF3IP3 facilitates the recruitment of STRN3 to the ER lumen through its transmembrane domain and fulfills its functional role in ER stress in an STRN3-dependent manner in LUAD cells. Given its dual role in orchestrating ER stress-associated apoptosis and autophagy in LUAD cell fate determination, the importance of TRAF3IP3 is highlighted as novel therapeutic target for LUAD treatment.

Autophagy regulates the development of Candida albicans (C. albicans) biofilms and their sensitivity to antifungals. Atg1, a serine/threonine protein kinase, recruits autophagy-related proteins for autophagosome formation. Atg9, the only transmembrane protein, is phosphorylated by Atg1 during autophagy. The specific roles of Atg1 and Atg9 in biofilm formation and resistance of C. albicans remain unclear. The study used RT-qPCR and Western blotting to assess the correlation between Atg1, Atg9 and biofilm formation, XTT reduction assays to evaluate biofilm formation and antifungal resistance, commercial kits to detect reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and autophagy activity, transmission electron microscopy (TEM) to study the morphological changes, protein-protein interaction (PPI) analysis to analyze the interaction between Atg1 and Atg9. Results demonstrated that Atg1 and Atg9 were highly expressed in biofilms than planktonic cells. Biofilm formation, antifungal resistance, MMP and autophagy activity decreased and ROS increased in atg1Δ/Δ and atg9Δ/Δ. TORC1 inhibition with rapamycin rescued the reduced biofilm formation of atg1Δ/Δ and increased antifungal resistance of atg1Δ/Δ and atg9Δ/Δ. PPI analysis and TEM observation indicated that Atg1 interacted with Atg9, which was certified by RT-qPCR and Western blotting. This study suggested that Atg1 interacts with Atg9, activates the autophagy regulating the formation and sensitivity of C. albicans biofilms.

Ca2+ overload is one of the most widely causes of inducing apoptosis, pyroptosis, immunogenic cell death, autophagy, paraptosis, necroptosis, and calcification of tumor cells, and has become the most valuable therapeutic strategy in the field of cancer treatment. Nevertheless, several challenges remain in translating Ca2+ overload-mediated therapeutic strategies into clinical applications, such as the precise control of Ca2+ dynamics, specificity of Ca2+ homeostasis dysregulation, as well as comprehensive mechanisms of Ca2+ regulation. Given this, we comprehensively reviewed the Ca2+-driven intracellular signaling pathways and the application of Ca2+-based biomaterials (such as CaCO3-, CaP-, CaO2-, CaSi-, CaF2-, and CaH2-) in mediating cancer diagnosis, treatment, and immunotherapy. Meanwhile, the latest researches on Ca2+ overload-mediated therapeutic strategies, as well as those combined with multiple-model therapies in mediating cancer immunotherapy are further highlighted. More importantly, the critical challenges and the future prospects of the Ca2+ overload-mediated therapeutic strategies are also discussed. By consolidating recent findings and identifying future research directions, this review aimed to advance the field of oncology therapy and contribute to the development of more effective and targeted treatment modalities.

Macroautophagy/autophagy, an evolutionarily conserved cellular degradation pathway, involves phagophores that sequester cytoplasmic constituents and mature into autophagosomes for subsequent lysosomal delivery. The ATG8 gene family, comprising the MAP1LC3/LC3 and GABARAP/GBR subfamilies in mammals, encodes ubiquitin-like proteins that are conjugated to phagophore membranes during autophagosome biogenesis. A central question in the field is how Atg8-family proteins are precisely involved in autophagosome formation, which remains controversial and challenging, at least in part due to the short lifespan of phagophores. In this study, we depleted the autophagosome closure regulator VPS37A to arrest autophagy at the vesicle completion step and determined the roles of mammalian Atg8-family proteins (mATG8s) in nutrient starvation-induced autophagosome biogenesis. Our investigation revealed that LC3 loss hinders phagophore formation, while GBR loss impedes both phagophore formation and expansion. The defect in membrane expansion by GBR loss appears to be attributed to compromised recruitment of ATG proteins containing an LC3-interacting region (LIR), including ULK1 and ATG3. Moreover, a combined deficiency of both LC3 and GBR subfamilies nearly completely inhibits phagophore formation, highlighting their redundant regulation of this process. Consequently, cells lacking all mATG8 members exhibit defects in downstream events such as ESCRT recruitment and autophagic flux. Collectively, these findings underscore the critical roles of mammalian Atg8-family proteins in phagophore formation and expansion during autophagy.Abbreviation: AIM: Atg8-family interacting motif; ADS: Atg8-interacting motif docking site; ATG: autophagy related; BafA1: bafilomycin A1; CL: control; ESCRT: endosomal sorting complex required for transport; FACS: fluorescence activated cell sorting; GBR: GABARAP; GBRL1: GABARAPL1; GBRL2: GABARAPL2; GBRL3: GABARAPL3; HKO: hexa-knockout; IP: immunoprecipitation; KO: knockout; LDS: LC3-interacting-region docking site; LIR: LC3-interacting region; mATG8: mammalian Atg8-family protein; MIL: membrane-impermeable ligands; MPL: membrane-permeable ligands; RT: room temperature; Stv: starved; TKO: triple-knockout; TMR: tetramethylrhodamine; UEVL: ubiquitin E2 variant-like; WCLs: whole cell lysates; WT: wild-type.

Rafeesome, a newly identified multivesicular body (MVB)-like organelle, forms through the fusion of RAB22A-mediated ER-derived noncanonical autophagosomes with RAB22A-positive early endosomes. However, the mechanism underlying the formation of RAB22A-mediated noncanonical autophagosomes remains unclear. Herein, we report a secretory ER-phagy pathway in which the assembly of RAB22A/TMEM33/RTN4 induces the clustering of high-molecular-weight RTN4 oligomers, leading to ER membrane remodeling. This remodeling drives the biogenesis of ER-derived RTN4-positive noncanonical autophagosomes, which are ultimately secreted as TMEM33-marked RAB22A-induced extracellular vesicles (R-EVs) via Rafeesome. Specifically, RAB22A interacts with the tubular ER membrane protein TMEM33, which binds to the TM2 domain of the ER-shaping protein RTN4, promoting RTN4 homo-oligomerization and thereby generating RTN4-enriched microdomains. Consequently, the RTN4 microdomains may induce high curvature of the ER, facilitating the bud scission of RTN4-positive vesicles. These vesicles are transported by ATG9A and develop into isolation membranes (IMs), which are then anchored by LC3-II, a process catalyzed by the ATG12-ATG5-ATG16L1 complex, allowing them to grow into sealed RTN4 noncanonical autophagosome. While being packaged into these ER-derived intermediate compartments, ER cargoes bypass lysosomal degradation and are directed to secretory autophagy via the Rafeesome-R-EV route. Our findings reveal a secretory ER-phagy pathway initiated by the assembly of RAB22A/TMEM33/RTN4, providing new insights into the connection between ER-phagy and extracellular vesicles.

Dysregulated autophagy has been implicated in the pathogenesis of numerous diseases, including cancer. Despite extensive research on the underlying mechanisms of autophagy, the involvement of long non-coding RNAs (lncRNAs) remains poorly understood. Here, we demonstrate that a previously identified lncRNA, HITT (HIF-1α inhibitor at the translation level), is closely associated with biological processes such as autophagy through unbiased bioinformatic analysis. Subsequent studies demonstrate that HITT is increased by several autophagic stimuli, including PI-103, a potent inhibitor of PI3K and mTOR. This is caused by a reduction in the binding between HITT and AGO2, resulting in a reduction in the activity of miR-205 towards HITT degradation. Increased HITT then binds to a key autophagy protein, Autophagy-related 5 (ATG5), and inhibits autophagosome formation by preventing the formation of the ATG12-ATG5-ATG16L1 complex. This results in HITT sensitizing PI-103-mediated cell death both in vitro and in vivo in nude mice by attenuating protective autophagy. The data presented herein demonstrate that HITT is a newly identified RNA regulator of autophagy and that it can be used to sensitize the colon cancer response to cell death by blocking the protective autophagy.

Autophagy-related (Atg) proteins catalyze autophagosome formation at the phagophore assembly site (PAS). The assembly of Atg proteins at the PAS follows a semihierarchical order, in which Atg8 is thought to be quite downstream but still able to control the size of autophagosomes. Yet, how Atg8 coordinates multiple branches of autophagy machinery to regulate autophagosomal size is not clear. Here, we show that, in yeast, Atg8 positively regulates the autophagy-specific phosphatidylinositol 3-OH kinase complex and the retrograde trafficking of Atg9 vesicles through interaction with Atg1. Mechanistically, Atg8 does not enhance the kinase activity of Atg1; instead, it recruits Atg1 to the surface of the phagophore likely to orient Atg1's activity toward select substrates, leading to efficient phagophore expansion. Artificial tethering of Atg1 kinase domains to Atg8s enhanced autophagy in yeast, human and plant cells and improved muscle performance in worms. We propose that Atg8-mediated relocation of Atg1 from the PAS scaffold to the phagophore is a critical step in positive autophagy regulation.

Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane autophagosome and its subsequent delivery to lysosomes for degradation and recycling. In Caenorhabditis elegans, autophagy participates in diverse processes such as stress resistance, cell fate specification, tissue remodeling, aging, and adaptive immunity. Genetic screens in C. elegans have identified a set of metazoan-specific autophagy genes that form the basis for our molecular understanding of steps unique to the autophagy pathway in multicellular organisms. Suppressor screens have uncovered multiple mechanisms that modulate autophagy activity under physiological conditions. C. elegans also provides a model to investigate how autophagy activity is coordinately controlled at an organismal level. In this chapter, we will discuss the molecular machinery, regulation, and physiological functions of autophagy, and also methods utilized for monitoring autophagy during C. elegans development.

Autophagy is a cellular degradation process reliant on lysosome, crucial for preserving intracellular homeostasis. The key saturated fatty acid palmitic acid (PA) has been demonstrated to exert regulatory effects on autophagic activity in mammals. However, the precise impact of PA on autophagy and its role in fish remains incompletely understood. Thus, this study aimed to investigate the regulation of PA on autophagy and explore the role of autophagy in inflammatory responses triggered by PA in the head kidney macrophages of large yellow croaker. This study indicates that PA exposure can inhibit macrophage autophagy by reducing the expression of genes related to autophagy (e.g., beclin1, ulk1, and lc3), activating the negative regulator mTORC1 signaling pathway (p70S6K and S6), and hindering autophagic flux. This effect was observed to be amplified with increasing exposure time and concentration of PA. Similarly to the in vitro results, the palm oil (PO) diet significantly reduced autophagic activity in the head kidney of the croaker in vivo. Subsequent studies demonstrated that restoring autophagy led to a notable reduction in the expression of PA and PO-induced pro-inflammatory genes (il-1β, il-6, tnf-α, and cox-2), the activation of the MAPK signaling pathway (p38 and JNK), and the NLRP3 inflammasome levels, both in vitro and in vivo. In contrast, further inhibition of autophagy produced the opposite effect in vitro. In conclusion, this study demonstrates that PA exerts a dynamic inhibitory effect on autophagy in the head kidney macrophage, which in turn promotes PA-induced inflammatory responses. These findings provide valuable insights into how PA influences autophagy and inflammatory responses in fish immune cells, contributing to the theoretical framework for improving the use of vegetable oils in aquaculture.

Bacterial invasion into the cytoplasm of epithelial cells triggers the activation of the cellular autophagic machinery as a defense mechanism, a process known as xenophagy. In this study, we identified HEATR3, an LC3-interacting region (LIR)-containing protein, as a factor involved in this defense mechanism using quantitative mass spectrometry analysis. HEATR3 localizes intracellularly invading Salmonella, and HEATR3 deficiency promotes Salmonella proliferation in the cytoplasm. HEATR3 also localizes to lysosomes damaged by chemical treatment, suggesting that Salmonella recognition is facilitated by damage to the host cell membrane. HEATR3 deficiency impairs LC3 recruitment to damaged membranes and blocks the delivery of the target to the lysosome. These phenotypes were rescued by exogenous expression of wild-type HEATR3 but not by the LIR mutant, indicating the crucial role of the HEATR3-LC3 interaction in the receptor for selective autophagy. HEATR3 is delivered to lysosomes in an autophagy-dependent manner. Although HEATR3 recruitment to the damaged membrane was unaffected by ATG5 or FIP200 deficiency, it was markedly impaired by treatment with a calcium chelator, suggesting involvement upstream of the autophagic pathway. These findings suggest that HEATR3 serves as a receptor for selective autophagy and is able to identify damaged membranes, facilitate the removal of damaged lysosomes, and target invading bacteria within cells.

Uveitis is a severe autoimmune eye disease that poses a significant threat to visual health. Autophagy is essential for maintaining cellular homeostasis and becomes dysregulated in autoimmune conditions like uveitis. MicroRNAs (miRNAs) can influence autophagy and apoptosis by targeting autophagy-related genes (Atg).

This study aimed to investigate the role of miR-30b-5p in regulating autophagy-related genes and to explore its therapeutic potential in experimental autoimmune uveitis (EAU).

EAU was induced and RT(Vega-Tapia et al., 2021 [2]) Profiler PCR Arrays were used to identify significant interactions among Atg genes and their role in uveitic pathogenesis. Both in vitro and in vivo experiments were used to assess the expression of Atg-related genes. Additionally, miR-30b-5p-carrying lentivirus injections were administered, and the levels of Atg5, Atg12, and Becn1 were measured, along with autophagosome formation through electron microscopy. Meanwhile, we also assessed inflammatory markers (i.e., IL-10, IL-17), the Th17/Treg ratio, and apoptosis.

In vitro experiments demonstrated that miR-30b-5p led to decreased expression of Atg5, Atg12, and Becn1, which resulted in a lower number of autophagosomes. In vivo validation confirmed these outcomes, showing reduced mRNA and protein levels of Atg-related molecules and diminished autophagosome formation after the injection of miR-30b-5p. Furthermore, miR-30b-5p exhibited anti-inflammatory effects by increasing IL-10 levels and decreasing IL-17, thereby improving the balance of the Th17/Treg ratio.

This study highlights the importance of autophagy in the pathogenesis of uveitis and identifies miR-30b-5p as a regulator of autophagy and inflammation. Targeting miR-30b-5p presents a promising therapeutic approach for treating uveitis.

Eukaryotic cells depend on their endolysosomal system for membrane protein and organelle turnover, plasma membrane quality control, or regulation of their nutrient uptake. All material eventually ends up in the lytic environment of the lysosome for cellular recycling. At endosomes and lysosomes, the multisubunit complexes CORVET and HOPS tether membranes by binding both their cognate Rab GTPase and specific membrane lipids. Additionally, they carry one Sec1/Munc18-like subunit at their center and thus promote SNARE assembly and, subsequently, bilayer mixing. Recent structural and functional analysis provided insights into their organization and suggested how these complexes combine tethering with fusion catalysis. This review discusses the function and structural organization of HOPS and CORVET in the context of recent studies in yeast and metazoan cells.

Transcriptional regulation of genes involved in the macroautophagy/autophagy-lysosome pathway acts as an important mechanism for controlling autophagy activity. The factors that globally regulate autophagy activity at the transcriptional level during C. elegans development remain unknown. Here we showed that the THAP domain-containing transcription factor LIN-15B modulates autophagy activity during C. elegans development. Loss of function of lin-15B suppresses the autophagy defect caused by impaired autophagosome maturation and promotes lysosome biogenesis and function. LIN-15B maintains the repressed state of genes involved in the autophagy pathway. Accordingly, loss of function of lin-15B upregulates a plethora of genes involved in autophagosome formation and maturation as well as lysosome biogenesis and function. The cytoplasm-to-nucleus translocation of LIN-15B is mediated by the T16G12.6/IMPORTIN 13/IPO-13 receptor and modulated by nutrient status. Our study uncovers that LIN-15B integrates environmental cues into transcriptional control of a network of genes involved in autophagy in C. elegans.Abbreviations: ATG: autophagy related; DIC: differential interference contrast; EPG: ectopic PGL granules; ER: endoplasmic reticulum; FOXO: forkhead box O; GFP: green fluorescent protein; SQST-1: SeQueSTosome related 1; SynMuv: synthetic multivulva; IPO-13: importin 13; TFEB: transcription factor EB.

In dimorphic yeasts, hyphal growth is primarily associated with infection and mycosis progression, with Trichosporon asahii causing deep-seated mycosis and summer-type hypersensitivity pneumonitis. Magnesium accelerates hyphal growth in T. asahii, leading to multi-septation, vacuolar expansion, and decreased lipid droplet size. However, the commonality of these phenotypes has not been studied in Trichosporonales yeasts. Therefore, to explore whether similar magnesium-induced phenotypes occur across Trichosporonales yeasts, we examined hyphal growth, multi-septation, vacuolar extension, and lipid droplet size and number in 30 species. Cell length increased with magnesium treatment in 13 yeasts: 5 Trichosporon (T. asahii, Trichosporon aquatile, Trichosporon asteroides, Trichosporon coremiiforme, and Trichosporon ovoides), three Apiotrichum (Apiotrichum brassicae, Apiotrichum montevideense, and Apiotrichum veenhuisii), three Cutaneotrichosporon (Cutaneotrichosporon cavernicola, Cutaneotrichosporon cutaneum, and Cutaneotrichosporon dermatis), Pascua guehoae, and Takashimella koratensis. C. dermatis also underwent pseudo-hyphal growth. Multi-septation increased in seven dimorphic yeasts, including five Trichosporon spp., Trichosporon faecale, and C. dermatis. The vacuolar area was significantly extended in T. asahii, T. aquatile, T. ovoides, and C. dermatis. Lipid droplet size increased only in Trichosporon inkin; however, it decreased in T. asahii, T. coremiiforme, and T. faecale. Additionally, lipid droplet number was preferentially altered in Apiotrichum and Cutaneotrichosporon. These results suggested that magnesium-induced multi-septation and vacuolar area expansion phenotypically distinguish Trichosporon hyphae from Apiotrichum and Cutaneotrichosporon hyphae and distinguish C. dermatis pseudo-hyphae from Cutaneotrichosporon spp. Moreover, differences in lipid droplet size can discriminate species within Trichosporon. Our results suggest that phenotypic alteration via magnesium treatment can contribute to the characterization of Trichosporonales yeasts. These findings provide insights into fungal pathogenesis and may support new treatment strategies.IMPORTANCEMagnesium sulfate considerably affects hyphal growth and cellular organization in Trichosporon asahii. To examine the commonality of this phenotype in Trichosporonales, we treated 30 Trichosporonales yeasts with magnesium sulfate and observed genus-level phenotypic alterations. Using cell length measurement, lipid droplet staining, septum staining, and vacuole staining, considerable hyphal diversity was observed among Trichosporonales. Notably, differences in the multi-septation phenotype and vacuolar size distinguished Trichosporon hyphae from Apiotrichum and Cutaneotrichosporon hyphae and distinguished Cutaneotrichosporon dermatis from other Cutaneotrichosporon spp. Moreover, differences in lipid droplet phenotype divided Trichosporon hyphae into two groups. Our study revealed the relationship between hyphal morphology and phylogenetic systematics in Trichosporonales.

During the hepatic histological progression in metabolic dysfunction-associated steatotic liver disease (MASLD), the immunological mechanisms play a the pivotal role, especially when progressing to metabolic dysfunction-associated steatohepatitis (MASH). The discovery of the stimulator of interferon genes (STING) marked a significant advancement in understanding the immune system.

We searched literature on STING involved in MASLD in PubMed to summarise the role of intrahepatic or extrahepatic STING signal pathways and the potential agonists or inhibitors of STING in MASLD.

Besides inflammation and type I interferon response induced by STING activation in the intrahepatic or extrahepatic immune cells, STING activation in hepatocytes leads to protein aggregates and lipid deposition. STING activation in hepatic macrophages inhibits autophagy in hepatocytes and promotes hepatic stellate cells (HSCs) activation. STING activation in HSCs promotes HSC activation and exacerbates liver sinusoidal endothelial cells (LSECs) impairment. However, it was also reported that STING activation in hepatic macrophages promotes lipophagy in hepatocytes and STING activation in HSCs leads to HSC senescence. STING activation in LSEC, inhibits angiogenesis. For extrahepatic tissue, STING signalling participates in the regulation of the intestinal permeability, intestinal microecology and insulin action in adipocytes, which were all involved in the pathogenesis of MASLD.

There're plenty of STING ligands in MASLD. How STING activation affects the intercellular conversation in MASLD deserves thorough investigation.

The ubiquitin-specific protease (USP) family is the largest and most diverse deubiquitinase (DUBs) family and plays a significant role in maintaining cell homeostasis. Dysregulation of USPs has been associated with carcinogenesis of various tumors. We identified that USP19 was downregulated in pancreatic tumor tissues and forced expression of USP19 diminished tumorigenicity of pancreatic cancer. Mechanistically, USP19 directly interacts with and stabilized NEK9 via inhibiting K48-specific polyubiquitination process on NEK9 protein at K525 site through its USP domain. Moreover, NEK9 phosphorylates the regulatory associated protein of mTOR (Raptor) at Ser792 and links USP19 to the inhibition of mTORC1 signaling pathway, which further leads to autophagic cell death of pancreatic cancer cells. Inhibition of autophagy by Atg5 knockdown or lysosome inhibitor bafilomycin A1 abolished the decreased malignant phenotype of USP19- and NEK9-overexpressing cancer cells. Importantly, USP19 expression exhibits a positive correlation with NEK9 expression in clinical samples, and low USP19 or NEK9 expression is associated with a worse prognosis. This study revealed that USP19-mediated NEK9 deubiquitylation is a regulatory mechanism for mTORC1 inhibition and provides a therapeutic target for diseases involving mTORC1 dysregulation.

Osteoarthritis (OA) is a degenerative disease which places an enormous burden on society, effective treatments are still limited. As a non-invasive and safe physical therapy, low-intensity pulsed ultrasound (LIPUS) can alleviate OA progression, but the underlying mechanism is not fully understood, especially the mechanical transduction between LIPUS and the organism. In this pioneering study, the biomechanical effects of LIPUS on living mice chondrocytes and living body zebrafish are investigate by using fluorescence imaging technology, to dynamically "visualize" its invisible mechanical stimuli in the form of calcium oscillations. It is also confirmed that LIPUS maintains cartilage homeostasis by promoting chondrocyte autophagy in a calcium-dependent manner. In addition, chondrocyte ion channels are screened by scRNA-seq and confirm that the mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) mediated the biological effects of LIPUS on chondrocytes. Finally, it is found that a combination of pharmacologically induced and LIPUS-induced Ca2+ influx in chondrocytes enhances the cartilage-protective effect of LIPUS, which may provide new insights for optimizing LIPUS in the treatment of OA.

Most of the knowledge on the mechanisms and functions of autophagy originates from studies in yeast and other cellular models. How this valuable information is translated to the brain, one of the most complex and evolving organs, has been intensely investigated. Fueled by the tight dependence of the mammalian brain on autophagy, and the strong links of human brain diseases with autophagy impairment, the field has revealed adaptations of the autophagic machinery to the physiology of neurons and glia, the highly specialized cell types of the brain. Here, we first provide a detailed account of the tools available for studying brain autophagy; we then focus on the recent advancements in understanding how autophagy is regulated in brain cells, and how it contributes to their homeostasis and integrated functions. Finally, we discuss novel insights and open questions that the new knowledge has raised in the field.

Macroautophagy is an important cellular process involving lysosomal degradation of cytoplasmic components, facilitated by autophagy-related proteins. In the protozoan parasite Toxoplasma gondii, autophagy has been demonstrated to play a key role in adapting to stress and the persistence of chronic infection. Despite limited knowledge about the core autophagy machinery in T. gondii, two PROPPIN family proteins (TgPROP1 and TgPROP2) have been identified with homology to Atg18/WIPI. Prior research in acute-stage tachyzoites suggests that TgPROP2 is predominantly involved in a non-autophagic function, specifically apicoplast biogenesis, while TgPROP1 may be involved in canonical autophagy. Here, we investigated the distinct roles of TgPROP1 and TgPROP2 in chronic stage T. gondii bradyzoites, revealing a critical role for TgPROP1, but not TgPROP2, in bradyzoite autophagy. Conditional knockdown of TgPROP2 did not impair bradyzoite autophagy. In contrast, TgPROP1 KO parasites had impaired autolysosome formation, reduced cyst burdens in chronically infected mice, and decreased viability. Together, our findings clarify the indispensable role of TgPROP1 to T. gondii autophagy and chronic infection.

It is estimated that up to a third of the human population is chronically infected with Toxoplasma gondii; however, little is known about how this parasite persists long term within its hosts. Autophagy is a self-eating pathway that has recently been shown to play a key role in parasite persistence, yet few proteins that carry out this process during T. gondii chronic infection are known. Here, we provide evidence for a non-redundant role of TgPROP1, a protein important in the early steps of the autophagy pathway. Genetic disruption of TgPROP1 resulted in impaired autophagy and chronic infection of mice. Our results reveal a critical role for TgPROP1 in autophagy and underscore the importance of this pathway in parasite persistence.

Biological membranes, primarily composed of phospholipid bilayers, are essential structures that compartmentalize the cell from the extracellular environment. The biosynthesis and regulation of membrane lipids have been extensively studied in model organisms such as Saccharomyces cerevisiae and mammalian cells. However, our understanding of biological membrane regulation in filamentous fungi, some of which are significant in medicine, pharmacy, and agriculture, remains limited. This minireview provides a comprehensive overview of the latest knowledge, focusing on filamentous fungi of Aspergillus species. Recent progress in understanding dynamic changes in membrane lipid profiles, driven by improvements in analytical techniques for lipidomics, is also presented. Furthermore, known that the cell morphology of filamentous fungi is closely linked to its harmful and beneficial characteristics, the influence of membrane composition on cell morphology is discussed. The integration of these findings will further enhance our understanding of the biological functions of membranes in filamentous fungi.

Muscle fiber is an important factor in beef quality. Here, we compared fast-type longissimus dorsi muscle and slow-type psoas major muscle from cattle using transcriptomic, proteomic and metabolomic analyses. A total of 1717 differentially expressed genes (DEGs), 297 differentially abundant proteins (DAPs) and 193 differentially abundant metabolites (DAMs) were identified between LD and PM tissue, respectively. For verification, we selected 10 DEGs for qRT-PCR and 6 DAPs for western blotting, and showed they were consistent between the two approaches. GO and KEGG enrichment analyses revealed that some DEGs, DAPs and DAMs were enriched in muscle fiber type-associated GO terms and pathways. Many of them are involved in glycolysis, TCA and fatty acid metabolism. Integrated multi-omics analysis showed a correlation coefficient of 0.6244 between the transcriptome and proteome. This study provides a new understanding of molecular mechanisms involved in the determination of bovine muscle fiber type and meat quality.

Metformin (Met), a well-known anti-diabetic drug with a potent autophagy induction property, has been proven to be effective against several parasitic diseases. In the present in vitro study, the effect of Met on the viability and ultrastructure of Schistosoma mansoni adults and juveniles in comparison with the standard anti-schistosomal drug, praziquantel (PZQ), was investigated. Adults and juveniles were treated in vitro with 5 µM PZQ and/or 10 mM Met. The viability of the treated worms was screened over a three-day period by light microscopy and recorded as mortality rates (MR). The alterations in the ultrastructure were verified using scanning and transmission electron microscopy. Met showed significant anti-schistosomal activity against both adults and juveniles and resulted in severe tegumental damage in the form of loss of integrity and architecture, with evident vacuolation suggestive of increased autophagy. Met might be a potential drug either alone or as an adjuvant to PZQ for the treatment of schistosomiasis mansoni and warrant its further assessment in animal models of disease.

Renal ischemia-reperfusion injury (IRI) is a common clinical condition that currently lacks effective treatment options. Inhibitors targeting the sodium-glucose co-transporter-2 (SGLT-2), recognized for their role in managing hyperglycemia, have demonstrated efficacy in enhancing the health outcomes for diabetic patients grappling with chronic kidney disease. Nevertheless, the precise impact of SGLT-2 inhibitors on renal ischemia-reperfusion injury (IRI) and the corresponding transcriptomic alterations remain to be elucidated. In our research, we developed a model of IRI using male C57BL/6 mice by clamping the unilateral renal artery and administering empagliflozin Transcriptomic alterations were analyzed using RNA sequencing (RNA-Seq), complemented by proteomic analysis to investigate the effects of empagliflozin. Histological assessments revealed increased renal inflammatory cell infiltration, widespread renal tubular injury, and elevated autophagosomes formation in the IRI group compared to controls. These pathological changes were significantly attenuated following empagliflozin treatment. Besides, renal function impairment can be alleviated in empagliflozin-treated group. RNA-Seq analysis identified lysosomal autophagy as a key biological process in IRI mice. Empagliflozin exerted a renoprotective effect by downregulating lysosome-associated membrane proteins, primarily LAMP1, LAMP2, and LAMP4 (CD68), through the PI3K-Akt, MAPK, and mTOR signaling pathways, thereby inhibiting autophagic processes. In conclusion, this study highlights enhanced inflammation and disrupted metabolism as hallmark transcriptomic signatures of renal. Furthermore, it demonstrates the renoprotective effects of empagliflozin in alleviating renal IRI by modulating autophagic processes.

Oligodendrocyte lineage cells, including oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLs), are essential in establishing and maintaining brain circuits. Autophagy is a conserved process that keeps the quality of organelles and proteostasis. The role of autophagy in oligodendrocyte lineage cells remains unclear. The present study shows that autophagy is required to maintain the number of OPCs/OLs and myelin integrity during brain aging. Inactivation of autophagy in oligodendrocyte lineage cells increases the number of OPCs/OLs in the developing brain while exaggerating the loss of OPCs/OLs with brain aging. Inactivation of autophagy in oligodendrocyte lineage cells impairs the turnover of myelin basic protein (MBP). It causes MBP to accumulate in the cytoplasm as multimeric aggregates and fails to be incorporated into integral myelin, which is associated with attenuated endocytic recycling. Inactivation of autophagy in oligodendrocyte lineage cells impairs myelin integrity and causes demyelination. Thus, this study shows autophagy is required to maintain myelin quality during aging by controlling the turnover of myelin components.

The objective of this study was to investigate the effect of oxidative stress induced by excessive Se on autophagy of sheep Leydig cells and its underlying mechanism. Leydig cells isolated from the testis of 8-month-old sheep were purified using a discontinuous Percoll density gradient. Cells were divided into four treatment groups (0, 2.0, 4.0 and 8.0 μmol/L of Se). After treatment with Se for 48 h, cell proliferation was detected by CCK-8 assay kit. The biochemical methods were used to evaluate the antioxidant status of Leydig cells. The mRNA transcript and protein abundance related to the AMPK-mTOR pathway and autophagy were detected by real-time PCR and western blot analysis. The results showed that the Leydig cells treated with 8.0 μmol/L Se have the lowest cell viability. The greater ROS content and lower GSH-Px activity were also observed in the Se8.0 group. The inclusion of 2.0 μmol/L Se in the medium did not affect the autophagy of Leydig cells. However, the relative abundance of ATG5 protein and LC3II/I ratio were elevated in the Se8.0 group. Oxidative stress induced by excessive Se (8.0 μmol/L) dramatically improved the abundance of key proteins related to AMPK-mTOR pathway and led to an increase of phosphorylated AMPK, mTOR and ULK1. Compared with the Se8.0 group, compound C could significantly inhibit the key molecules of AMPK-mTOR signaling pathway and mitigate the autophagy of Leydig cells induced by excessive Se. These results indicate that appropriate Se (2.0 μmol/L) can enhance the viability of sheep Leydig cells. Oxidative stress caused by Se excess can induce cell autophagy via activating AMPK-mTOR signaling pathway. The existed crosstalk between autophagy and apoptosis could decide the fate of Leydig cells. This process could play a decisive role in the maintenance of normal male fertility and spermatogenesis by affecting the number of Leydig cells in testis.

ATG1 stimulates autophagy biogenesis and serves as a gatekeeper for classical autophagy. To obtain insight into the control of autophagy by ATG1 and determine whether ATG1 has broader processes, we performed a thorough proteomics analysis on the Col-0 wild-type and atg1abct mutant in Arabidopsis thaliana. Proteomic data analysis pointed out that ATG1 has an unidentified function within the inositol trisphosphate and fatty acid metabolism. We also discovered ATG1-dependent autophagy has an emerging connection with ER homeostasis and ABA biosynthesis. Moreover, Gene Ontology terms for abiotic and biotic stress were strongly enriched in differentially abundant proteins, consistent with the reported role of canonical autophagy in these processes. Additional physiological and biochemical analysis revealed that atg1abct exhibited stronger drought resistance under both PEG-simulated drought treatment and natural drought stress. Results from DAB staining also indicated that atg1abct accumulation fewer ROS than Col-0 following drought treatment. As a result, these results illuminate previously unknown functions for ATG1 and offers novel perspectives into the underlying processes of autophagy function.

Background: Hepatic fibrosis is a major global health issue without an optimal drug treatment, highlighting the urgent need to find effective therapies. This study aimed to clarify the role and mechanism of micheliolide in treating hepatic fibrosis. Methods: The efficacy of MCL was evaluated in a mouse model of CCl4-induced hepatic fibrosis. LX-2 cells were subjected to MCL treatment, and subsequent changes in fibrosis markers, autophagy, and the MEK/ERK pathway were analyzed using transcriptomics and Western blotting. The interaction between MCL and TrxR1 or TrxR2 were validated using cellular thermal shift assays (CETSA) and drug affinity responsive target stability (DARTS) assays. Results: Our findings indicated that MCL significantly alleviated CCl4-induced hepatic fibrosis, improved liver function, and downregulated the expression of fibrosis markers. Additionally, MCL significantly inhibited LX-2 cell activation by suppressing cell proliferation, extracellular matrix (ECM) production, and autophagy, while activating the MEK/ERK pathway. Moreover, MCL elevated intracellular and mitochondrial reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential, and altered mitochondrial morphology. The ROS scavenger N-acetylcysteine (NAC) attenuated MCL-induced MEK/ERK pathway activation and increased collagen type I alpha 1 (COL1A1) and fibronectin (FN) expression. Further analysis confirmed that MCL directly interacts with TrxR1 and TrxR2, leading to the inhibition of their enzymatic activities and the induction of ROS generation. Ultimately, MCL attenuated the fibrotic process and autophagic flux in LX-2 cells. Conclusions: The findings of our study confirmed that MCL has the potential to alleviate hepatic fibrosis, thereby introducing a novel candidate drug and therapeutic strategy for management of this condition.