Protein Degradation Research Articles

Genome-wide association study of metabolic traits in the giant duckweed Spirodela polyrhiza.

The exceptionally high growth rate and high flavonoid content make the giant duckweed Spirodela polyrhiza (L.) Schleid. (Arales: Lemnaceae Martinov) an ideal organism for food production and metabolic engineering. To facilitate this, identification of the genetic basis underlying growth and metabolic traits is essential. Here, we analysed growth and content of 42 metabolites in 137 S. polyrhiza genotypes and characterized the genetics underpinning these traits using a genome-wide association (GWA) approach. We found that biomass positively correlated with the content of many free amino acids, including L-glutamine, L-tryptophan, and L-serine, but negatively correlated with specialized metabolites, such as flavonoids. GWA analysis showed that several candidate genes involved in processes such as photosynthesis, protein degradation, and organ development were jointly associated with multiple metabolic traits. The results suggest the above genes are suitable targets for simultaneous optimization of duckweed growth and metabolite levels. This study provides insights into the metabolic diversity of S. polyrhiza and its underlying genetic architecture, paving the way for industrial applications of this plant via targeted breeding or genetic engineering.

Polyphenols and Their Biogenic Nano-Formulations Targeting BACE1 as Anti-Amyloid Therapies; Meeting the Challenges of Bioavailability, Safety, and Specificity for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD), a progressiveneurodegenerative condition is marked by extensive damage in the brain and dementia. Among the pathological hallmarks of AD is beta-amyloid (Aβ). Production of toxic Aβ oligomers production and accumulation in the brain is among the characteristic features of the disease. The abnormal accumulation Aβ is initiated by the catalytic degradation of Amyloid Precursor Proteins (APP) by Beta Amyloid Cleaving Enzyme 1 (BACE1) to generate insoluble amyloid plaques. The abnormal proteins are mitochondrial poison which disrupt the energy production and liberate excessive free radicals causing neuronal damage and mutations. Consequently, targeting Aβ-associated pathways has become a focus in the pursuit of developing effective AD treatments. An obstacle faced by many medications used to treat neurodegenerative diseases (NDs) is the restricted permeability across the blood-brain barrier (BBB). Unfortunately, no anti-amyloid drug is clinically approved till now. Recent advancements in nanotechnology have provided a possible solution for delivering medications to specific targets. By integrating natural products with nano-medicinal approaches, it is possible to develop novel and highly efficient therapeutic strategies for the treatment of AD.

Aptamer and N-Degron Ensemble (AptaGron) as a Target Protein Degradation Strategy.

Target protein degradation (TPD) is a promising strategy for catalytic downregulation of target proteins through various cellular proteolytic pathways. Despite numerous reports on novel TPD mechanisms, the discovery of target-specific ligands remains a major challenge. Unlike small-molecule ligands, aptamers offer significant advantages, owing to their SELEX-based systematic screening method. To fully utilize aptamers for TPD, we designed an aptamer and N-degron ensemble system (AptaGron) that circumvents the need for synthetic conjugations between aptamers and proteolysis-recruiting units. In our AptaGron system, a peptide nucleic acid containing an N-degron peptide and a sequence complementary to the aptamer was designed. Using this system, we successfully degraded three target proteins, tau, nucleolin, and eukaryotic initiation factor 4E (eIF4E), which lack specific small-molecule ligands. Our results highlight the potential of the AptaGron approach as a robust platform for targeted protein degradation.

Engineered platelets as targeted protein degraders and application to breast cancer models.

Clinical application of chimeric molecules for targeted protein degradation has been limited by unfavorable drug-like properties and biosafety concerns arising from nonspecific biodistribution after systemic administration. Here we develop a method to engineer platelets for degradation of either intracellular or extracellular proteins of interest (POIs) in vivo by covalently labeling heat shock protein 90 (HSP90) in platelets with a POI ligand. The degrader platelets (DePLTs) target wound areas and undergo activation. Depending on the tethered POI ligand and transport mechanism of the prelabeled HSP90, activated DePLTs can mediate targeted protein degradation in the target cell through the ubiquitin-proteasome machinery or the lysosome. HSP90 packaged into platelet-derived microparticles uses the ubiquitin-proteasome system to degrade intracellular POIs, whereas released free HSP90 redirects extracellular POIs to lysosomal degradation. In postsurgical breast cancer mouse models, DePLTs engineered with corresponding POI ligands effectively degrade intracellular bromodomain-containing protein 4 or extracellular programmed cell death ligand 1, thereby suppressing cancer recurrence or metastasis.

Discovery of a molecular glue for EGFR degradation.

Aberrant expression of epidermal growth factor receptor (EGFR) plays a critical role in the pathogenesis of various tumors, potentially representing a target for therapeutic intervention. Nonetheless, EGFR remains a challenging protein to target pharmacologically in triple-negative breast cancer (TNBC). An emerging approach to address the removal of such proteins is the application of molecular glue (MG) degraders. These compounds facilitate protein-protein interactions between a target protein and an E3-ubiquitin ligase, subsequently leading to protein degradation. Herein, we identified a new MG (CDDO-Me, C-28 methyl ester of 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid), which orchestrated binding between EGFR and KEAP1 (an E3-ubiquitin ligase adapter), thereby initiating the ubiquitination and degradation of EGFR. CDDO-Me directly interacted with the tyrosine kinase (TK) domain of EGFR, resulting in its degradation via an autophagy-dependent lysosomal pathway. Knockdown of KEAP1 decreased the degradation of EGFR by reducing its K63-linked ubiquitination, leading to diminished EGFR colocalization in autophagosomes and lysosomes. Notably, CDDO-Me attenuates TNBC progression by accelerating EGFR degradation in cell-derived xenografts and patient-derived organoid models, highlighting its clinical application potential. Consequently, induction of EGFR degradation through MG degraders represents a viable therapeutic strategy for TNBC.

Proteolytic platelets as targeted protein degraders.

Proteolytic platelets as targeted protein degraders.

Dysregulation of protein degradation and alteration of secretome in α-synuclein-exposed astrocytes: implications for dopaminergic neuronal dysfunction

BackgroundA key factor in the propagation of α-synuclein pathology is the compromised protein quality control system. Variations in membrane association and astrocytic uptake between different α-synuclein forms suggest differences in exocytosis or membrane cleavage, potentially impacting the secretome's influence on dopaminergic neurons. We aimed to understand differences in protein degradation mechanisms of astrocytes for both wild-type (WT) and mutant forms of α-synuclein, specifically during periods of reduced degradation efficiency. We also investigated α-synuclein release into the secretome and its effects on healthy dopaminergic neurons.MethodsCellular models used were rat primary astrocytes alongside hiPSC-derived astrocytes, whose impact on rat primary dopaminergic neurons and the human SH-SY5Y cell line was investigated. We examined the release and accumulation of α-synuclein resulting from impaired degradatory pathways, including matrix metalloprotease-MMP9, the ubiquitin proteasomal pathway-UPS, and the autophagy-lysosomal pathway-ALP, using immunocytochemical analysis and flow cytometry. Additionally, we explored the effect of astrocytic secretome on dopaminergic-neuronal survival, neurite collapse and function.ResultsAt early stages, astrocytes were able to deal efficiently with monomeric α-synuclein (via UPS), and larger aggregates (through MMP9 and autophagy), clearing extracellular α-synuclein and maintaining neuronal health. However, extended exposure to extracellular monomeric and aggregated α-synuclein compromised their proteasomal activity, inhibiting MMP9 and destabilizing autophagy, transforming astrocytes from protectors to promoters of neurodegeneration. This study is the first to elucidate the astrocytes' preferred degradation pathways for both monomeric and aggregated forms of α-synuclein, along with the subsequent effects of these payloads on the cellular degradation machinery. The astrocytic transformation is characterized by α-synuclein expulsion, increased release of inflammatory cytokines, and diminished secretion of growth factors leading to dopaminergic neuronal apoptosis and dysfunction, particularly neurite collapse, intracellular Ca2+ response and vesicular dopamine release. The presence of phosphorylated and nitrated α-synuclein species in astrocytes also suggests their potential involvement in modifying both forms of the protein.ConclusionThe initial protective action of astrocytes in clearing and degrading extracellular α-synuclein is severely compromised at latter stages, leading to astrocytic dysfunction and impairing neuron-glia cross-talk. This study underscores the criticality of integrating astrocytes into treatment paradigms in synucleinopathies.

The co-chaperone DNAJA2 buffers proteasomal degradation of cytosolic proteins with missense mutations

Mutations can disrupt a protein's native function by causing misfolding, which is generally handled by an intricate protein quality control network. To better understand the triaging mechanisms of misfolded cytosolic proteins, we screened a human mutation library to identify a panel of unstable mutations. The degradation of these mutated cytosolic proteins is largely dependent on the ubiquitin proteasome system. Using BioID proximity labelling, we found that the co-chaperones DNAJA1 and DNAJA2 are key interactors with one of the mutated proteins. Notably, the absence of DNAJA2 increases the turnover of the mutant but not the wild-type protein. Our work indicates that specific missense mutations in cytosolic proteins can promote enhanced interactions with molecular chaperones. Assessment of the broader panel of cytosolic mutant proteins shows that the co-chaperone DNAJA2 exhibits two distinct behaviours: acting to stabilize a wide array of cytosolic proteins including wild type variants, and specifically “buffer” some mutant proteins to reduce their turnover. Our work illustrates how distinct elements of the protein homeostasis network are utilized in the presence of a cytosolic misfolded protein.

Protein Dynamics in Plant Immunity: Insights into Plant–Pest Interactions

All living organisms regulate biological activities by proteins. When plants encounter pest invasions, the delicate balance between protein synthesis and degradation becomes even more pivotal for mounting an effective defense response. In this review, we summarize the mechanisms by which plants regulate their proteins to effectively coordinate immune responses during plant–pest interactions. Additionally, we discuss the main pathway proteins through which pest effectors manipulate host protein homeostasis in plants to facilitate their infestation. Understanding these processes at the molecular level not only deepens our knowledge of plant immunity but also holds the potential to inform strategies for developing pest-resistant crops, contributing to sustainable and resilient agriculture.

A Biomolecular Circuit for Automatic Gene Regulation in Mammalian Cells with CRISPR Technology.

We introduce a biomolecular circuit for precise control of gene expression in mammalian cells. The circuit leverages the stochiometric interaction between the artificial transcription factor VPR-dCas9 and the anti-CRISPR protein AcrIIA4, enhanced with synthetic coiled-coil domains to boost their interaction, to maintain the expression of a reporter protein constant across diverse experimental conditions, including fluctuations in protein degradation rates and plasmid concentrations, by automatically adjusting its mRNA level. This capability, known as robust perfect adaptation (RPA), is crucial for the stable functioning of biological systems and has wide-ranging implications for biotechnological applications. This system belongs to a class of biomolecular circuits named antithetic integral controllers, and it can be easily adapted to regulate any endogenous transcription factor thanks to the versatility of the CRISPR-Cas system. Finally, we show that RPA also holds in cells genomically integrated with the circuit, thus paving the way for practical applications in biotechnology that require stable cell lines.

Ubiquitin Ligase U-Box51 Positively Regulates Drought Stress in Potato (Solanum tuberosum L.)

The ubiquitin-proteasome system (UPS) is a key protein degradation pathway in eukaryotes, in which E3 ubiquitin ligases mediate protein ubiquitination, directly or indirectly targeting substrate proteins to regulate various biological processes, including plant growth, hormone signaling, immune responses, and adaptation to abiotic stress. In this study, we identified plant U-box protein 51 in Solanum tuberosum (StPUB51) as an E3 ubiquitin ligase through transcriptomic analysis, and used it as a candidate gene for gene-function analysis. Quantitative real-time PCR (qRT-PCR) was used to examine StPUB51 expression across different tissues, and its expression patterns under simulated drought stress induced by polyethylene glycol (PEG 6000) were assessed. Transgenic plants overexpressing StPUB51 and plants with down-regulated StPUB51 expression were generated to evaluate drought tolerance. The activities of key antioxidant enzymes-superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) as well as malondialdehyde (MDA) content in transgenic plants’ leaves were measured under drought conditions. Protein–protein interactions involving StPUB51 were explored via yeast two-hybrid (Y2H) screening, with interaction verification by bimolecular fluorescence complementation (BiFC). StPUB51 was predominantly expressed in stems, with lower expression observed in tubers, and its expression was significantly upregulated in response to 20% PEG-6000 simulated drought. Subcellular localization assays revealed nuclear localization of the StPUB51 protein. Under drought stress, StPUB51-overexpressing plants exhibited enhanced SOD, POD, and CAT activities and reduced MDA levels, in contrast to plants with suppressed StPUB51 expression. Y2H and BiFC analyses identified two interacting proteins, StSKP2A and StGATA1, which may be functionally linked to StPUB51. Collectively, these findings suggest that StPUB51 plays a positive regulatory role in drought tolerance, enhancing resilience in potato growth and stress adaptation.

Host-specific effects of Eubacterium species on Rg3-mediated modulation of osteosarcopenia in a genetically diverse mouse population

BackgroundOsteosarcopenia, characterized by the simultaneous loss of bone and muscle mass, is a serious health problem in the aging population. This study investigated the interplay between host genetics, gut microbiota, and musculoskeletal health in a mouse model of osteosarcopenia, exploring the therapeutic potential of gut microbiota modulation.MethodsWe examined the effects of Rg3, a phytochemical, on osteosarcopenia and its interactions with host genetics and gut microbiota in six founder strains of the Collaborative Cross (CC) population. Subsequently, we evaluated the therapeutic potential of Eubacterium nodatum (EN) and Eubacterium ventriosum (EV), two gut microbes identified as significant correlates of Rg3-mediated osteosarcopenia improvement, in selected C57BL/6 J (B6) and 129S1/SvImJ (129S1) mouse strains.ResultsRg3 treatment altered gut microbiota composition aligned with osteosarcopenia phenotypes, which response varied depending on host genetics. This finding enabled the identification of two microbes in the Eubacterium genus, potential mediator of Rg3 effect on osteosarcopenia. Oral administration of EN and EV differentially impacted bone density, muscle mass, exercise performance, and related gene expression in a mouse strain-specific manner. In 129S1 mice, EN and EV significantly improved these parameters, effectively reversing osteosarcopenic phenotypes. Mechanistic investigations revealed that these effects were mediated through the modulation of osteoblast differentiation and protein degradation pathways. In contrast, EN and EV did not significantly improve osteosarcopenic phenotypes in B6 mice, although they did modulate mitochondrial biogenesis and microbial diversity.ConclusionsOur findings underscore the complex interplay between host genetics and the gut microbiota in osteosarcopenia and emphasize the need for personalized treatment strategies. EN and EV exhibit strain-specific therapeutic effects, suggesting that tailoring microbial interventions to individual genetic backgrounds may be crucial for optimizing treatment outcomes.9Nfyi13u2tifXMNNi2cAAqVideo Graphical

ESCRT mediates micronucleophagy and macronucleophagy in yeast

Endosomal sorting complex required for transport (ESCRT) is required for maintenance of nuclear functions and prevention of neurodegenerative diseases. The budding yeast Saccharomyces cerevisiae is an ideal model for studying ESCRT-dependent diseases. Nucleolar proteins are degraded by macronucleophagy and micronucleophagy after nutrient depletion and inactivation of target of rapamycin complex 1 (TORC1) kinase. Here, we show that ESCRT is critical for micronucleophagic degradation of nucleolar proteins upon TORC1 inactivation. In addition, ESCRT was also critical for rDNA condensation and nucleolar remodeling, which is necessary for proper micronucleophagic degradation of nucleolar proteins after TORC1 inactivation. On the other hand, ESCRT was dispensable for bulk macroautophagy, whereas it was also critical for macronucleophagy. Thus, ESCRT has an important role for elimination of nucleolar proteins in response to nutrient deprivation.

Anthricin-induced hyperactive proteasome and its molecular mechanism

Recently, targeted protein degradation has attracted increasing interest as a new drug discovery approach. This method aims to control the function of drug targets by inducing their degradation through protein degradation systems such as the proteasome. Concurrently, compounds that enhance proteasome activity have also garnered attention. In 2023, we reported that anthricin (also known as 4-deoxypodophyllotoxin), a natural product that belongs to the lignan family, enhances proteasome activity. However, whether this enhancement was because of increased proteasome expression or improved proteasome function remains unclear. In this study, we investigated the structure–activity relationship of anthricin and its analogs in enhancing proteasome activity, the effects of anthricin on proteasome-related gene expression, and the direct binding between anthricin and the proteasome using pull-down assay. Moreover, we assessed the interaction between anthricin and the proteasome using molecular dynamics (MD) simulations. The results showed that anthricin does not induce proteasome-related gene expression, but instead binds to the β-subunit of the proteasome, bringing the side chains of three amino acid residues (Thr1, Asp17, and Lys33) at the catalytic site closer together, thereby inducing a hyperactive state. To the best of our knowledge, this study is the first to suggest the mechanism of proteasome activity enhancement by anthricin at the molecular level. The findings could contribute to the development of new chemotypes to enhance the effects of targeted protein degraders by regulating proteasome activity.

Snake venom weakens neurovascular integrity and promotes vulnerability to neuroinflammation

Snake envenomation poses significant medical challenges, particularly in subtropical and tropical regions, with long-term impacts on neurovascular integrity and neuroinflammation remaining underexplored. This study investigates the effects of venom from four species of venomous snakes in southern China—Zhoushan Cobra (Naja atra, NA), Many-banded Krait (Bungarus multicinctus, BM), Five-paced Pit Viper (Deinagkistrodon acutus, DA), and Chinese Moccasin (Protobothrops mucrosquamatus, PM) — on the blood–brain barrier (BBB) and chronic neuroinflammation. Using mass spectrometry, we analyzed venom protein compositions, while cytotoxic effects on mouse brain endothelial cells (bEND.3) were evaluated to determine IC50 values. In vitro BBB models and in vivo experiments in C57BL/6J mice revealed that NA venom, in particular, significantly compromised BBB integrity without inducing large-scale apoptosis, leading to persistent BBB disruption characterized by increased permeability and selective degradation of extracellular matrix and tight junction proteins. Moreover, to simulate secondary infections that often occur following snakebites, we combined venom exposure with lipopolysaccharide (LPS) treatment, which exacerbated neuroinflammatory responses by intensifying microglial activation and promoting a pro-inflammatory phenotype. These findings highlight the role of snake venom in compromising neurovascular integrity and promoting vulnerability to chronic neuroinflammation, emphasizing the need for further research into venom-induced neuroinflammatory pathways and their potential as therapeutic targets.

Comparison of the effects of taurine and methionine supplementation on the nitrogen metabolism of beef steers elucidated through plasma metabolome profiling

The objectives of the experiment were to compare the effects of rumen-protected taurine (RPT) and rumen-protected methionine (RPM) on the nitrogen (N) metabolism, plasma biochemical parameters, and metabolomics in beef steers and to clarify whether taurine plays similar roles as methionine (Met) in improving the regulation of N metabolism in beef steers. Six Simmental steers aged 12 months (liveweight 325 ± 7 kg) were used as experimental animals. The experimental treatments included a basal diet, the basal diet + 70.0 g/d RPT and the basal diet + 74.2 g/d RPM. The treatments were assigned in a replicated 3 × 3 Latin square design. Each experimental period included 15 d of adaptation and 5 d of sampling. The results showed that supplementing the diet with RPT or RPM did not affect the apparent nutrient digestibility (P > 0.05). Supplementing the diet with RPT or RPM increased the N retention (P < 0.05) and the N utilization efficiency (NUE) (P < 0.05) and decreased the urinary excretion of 3-Methylhistidine (P < 0.05) and the estimated skeletal protein degradation rate (P < 0.05). Supplementing the diet with RPT increased the plasma concentrations of taurine (P < 0.001), cysteine (P = 0.010), valine (P = 0.013) and total non-essential amino acids (NEAA) (P = 0.047) and tended to increase the plasma concentrations of essential amino acids (EAA) + NEAA (P = 0.087), but it did not affect the plasma concentrations of total EAA (P > 0.05). Supplementing the diet with RPM increased the plasma concentrations of methionine (P = 0.033), lysine (P = 0.047), cysteine (P = 0.007), leucine (P = 0.046), isoleucine (P = 0.046), valine (P = 0.034), total EAA (P = 0.028), total NEAA (P = 0.004) and EAA + NEAA (P = 0.004). The plasma metabolomics profiling revealed that supplementing the diet with RPT upregulated the plasma concentrations of taurine (P < 0.001), L-Cysteine (P = 0.004) and some amino acid (AA) analogues (P < 0.05) and RPM upregulated the plasma concentrations of Met (P = 0.021), L-Isoleucine (P = 0.036), L-Tryptophan (P = 0.006) and some AA analogues (P < 0.05). In conclusion, taurine has similar impacts to Met in improving the N retention and the NUE in beef steers. Taurine deficiency is one of the main reasons that the NUE of beef steers is low. Supplementation of the diet with taurine is beneficial to the N utilization in beef steers.

Discovery of potent hypoxia-inducible factor-1α (HIF-1α) degraders by proteolysis targeting chimera (PROTAC)

Under hypoxic conditions in tumor cells, HIF-1α is unable to bind to VHL E3 ligase due to the blocked hydroxylation reaction, resulting in impaired degradation and intracellular accumulation. Mounting evidences show a close association between HIF-1α overexpression and drug resistance, treatment failure, and increased mortality. To address this, we innovatively introduced an E3 ligase ligand to the HIF-1α inhibitor IDF-11774 using the PROTACs strategy, aiming to reactivate the degradative pathway impeded under hypoxia, and thereby achieve the redegradation of HIF-1α protein. Western blotting analyses demonstrated that most of we synthesized compounds effectively degraded HIF-1α. Among these, compounds C3 and V2 exhibited excellent anti-proliferation activity on 231 cells with IC50 values of 48.98 μM and 7.54 μM, respectively. Both compounds induced protein degradation in a concentration-dependent manner, achieving degradation rates up to 80 %. Additionally, this degradation was inhibited by the proteasome inhibitor MG132. As a part of the ongoing effort to develop HIF-1 inhibitors, targeting the degradation of HIF-1α may offer an effective treatment against solid tumors.

Evaluating the efficacy of citrus fruit peel extract in preserving the quality of silver carp (Hypophthalmichthys molitrix) surimi during frozen storage

This research investigated the effects of mosambi peel extract (MPE) on the stability of proteins and textural characteristics of silver carp surimi during frozen storage at -20°C. The findings revealed that surimi fortified with 0.75% MPE displayed upgraded protein solubility (PS), water holding capacity (WHC), Ca2+-ATPase activity, and sulfhydryl (SH) content. It also exhibited reduced levels of total carbonyls and surface hydrophobicity, along with higher overall acceptability compared to surimi treated with synthetic cryoprotectants (control) throughout storage. Additionally, MPE slowed down the increase in total volatile basic nitrogen (TVBN) and protein degradation index (PI), as evidenced by SDS-PAGE showing higher intensities of myosin heavy chain (MHC) and actin over the storage period. Moreover, the incorporation of MPE effectively mitigated lipid oxidation as peroxide value (PV), and thiobarbituric acid (TBA) were lesser than control. Fourier-transform infrared spectroscopy (FTIR) peaks specified that the relative content of α-helix and β-sheet structures remained more stable in the MPE-treated group compared to the control, along with the improved gel and textural properties of surimi. Hence, this study suggests that 0.75% MPE could serve as a natural alternative to synthetic cryoprotectants, ensuring the oxidative stability of silver carp surimi during frozen storage while enriching it with beneficial bioactive compounds.

Triticain alpha represents the major active papain-like cysteine protease in naturally senescing and ozone-treated leaves of wheat

Current background tropospheric ozone (O3) concentrations have significant adverse effects on wheat. O3 generally induces oxidative damages and premature leaf senescence leading to important yield losses. As leaf protein degradation and recycling is involved in both maintaining cell longevity during abiotic stresses and performing efficient nitrogen remobilization during senescence, we aimed to identify proteases involved in acidic endoproteolytic activities during natural and O3-induced leaf senescence in wheat. Field-grown plants of two winter wheat cultivars were exposed to ambient and semi-controlled chronic O3 concentrations, from pre-anthesis to grain harvest. Yield parameters were impacted by the most elevated O3 exposure for both cultivars. At the cellular level, our analysis revealed that both natural leaf senescence and O3 treatments induced a stimulation of acidic (pH 5.5) endoproteolytic activities, mostly due to papain-like cysteine proteases (PLCPs). Identification of active PLCPs using activity-based protein profiling (ABPP) revealed that Triticain α was the major active PLCP in senescing flag leaves and the only PLCP whose abundance increased with O3 stress, a result of positive transcriptional regulation. Our study provides novel insight into the implication of PLCP-mediated proteolysis in O3 sensitivity in a major crop.

PROTAC-mediated FTO protein degradation effectively alleviates diet-induced obesity and hepatic steatosis

Demethylation of N6-Methyladenosine (m6A) by fat mass and obesity-associated protein (FTO) occurs in the development of obesity and fatty liver disease. In this study, we synthesized FTO-degradation targeted chimera (FTO-DT), which exhibited excellent lipid-lowering activity at low concentration. At a concentration of 0.33 nM, the FTO-DT continuously and efficiently degraded FTO protein and reduced fat deposition. The FTO-DT improved energy metabolism and oxidative stress by increasing intracellular m6A levels, and further reduced fat deposition in hepatocytes, adipocytes, and mice fed a high-fat diet. The findings support the potential of FTO degradation by FTO-DT as a therapy for obesity and metabolic-associated fatty liver disease (MAFLD). This study provides a theoretical basis for the application of PROTACs in the treatment of metabolic disease and describes a novel approach for the development of drugs targeting metabolic disorders.