Chronic kidney disease (CKD) remains a significant global health burden, with hypertensive nephropathy (HN) as one of its primary causes. Podocyte injury is a key factor in the progression of CKD. However, the molecular mechanisms underlying angiotensin II-induced podocyte injury remain incompletely understood. Ubiquitin-specific protease 22 (USP22) has been reported to facilitate a range of cellular processes, including cell proliferation and apoptosis. However, the role of USP22 in HN pathogenesis is unclear.

The expression of USP22 was assessed in kidney samples from hypertensive nephropathy patients, angiotensin II-induced hypertensive nephropathy mouse models, and cultured podocytes treated with angiotensin II. Podocyte-specific USP22 knockout mice were used to investigate the effects of USP22 deletion on podocyte injury and inflammation.

USP22 expression was significantly upregulated in kidneys of HN patients, angiotensin II-induced mouse models, and cultured podocytes. Podocyte-specific deletion of USP22 markedly reduced angiotensin II-induced podocyte injury and inflammatory responses. Furthermore, we identified high-mobility group box protein 1 (HMGB1) as a protein that interacts with USP22. USP22 deubiquitinated and stabilized HMGB1 through K48-linked ubiquitination. Downregulation of USP22 expression improved kidney function and pathological changes in HN by promoting HMGB1 degradation.

This study identifies USP22 as a key regulator of angiotensin II-induced podocyte injury and inflammation through its interaction with HMGB1. Our findings revealed that following glomerular injury, damage and shedding of tubular cells also occurred. Targeting the USP22-HMGB1 axis offers a promising therapeutic strategy for treating hypertensive nephropathy and other types of CKD.

Intestinal ischemia/reperfusion (I/R) is a severe pathophysiological process that occurs in a variety of clinical conditions and can trigger multiple life-threatening syndromes. Intestinal I/R is associated endoplasmic reticulum (ER) stress. Prolyl 4-hydroxylase subunit beta (P4HB) contributes significantly to maintaining ER redox homeostasis, which is affected by I/R injury. Nevertheless, the molecular mechanism of P4HB expression and function in intestinal I/R is still unknown. In our study, we discovered that the expression of P4HB was clearly downregulated in the intestine of mice at the reperfusion stage and in Caco2 cells at the reoxygenation stage. In addition, P4HB-knockdown mice exhibited clearly enhanced ER stress-mediated apoptosis of intestinal tissue under intestinal I/R, whereas P4HB overexpression in Caco2 cells alleviated ER stress-mediated apoptosis under HR. Furthermore, via bioinformatics screening of proteins that interact with P4HB, ubiquitin-specific protease 5 (USP5) was identified as a critical factor in the abnormal expression of P4HB. USP5 interacts with P4HB and remains stable by removing ubiquitin. In vivo, P4HB knockdown counteracted the effect of USP5 overexpression on alleviating ER stress-mediated apoptosis in response to intestinal I/R. In summary, this study revealed that P4HB plays a crucial role in regulating ER stress-mediated apoptosis and identified USP5, which is a novel mediator of P4HB, as a prospective target for the treatment of intestinal I/R.

Recent studies have implicated altered ubiquitination/de-ubiquitination pathway in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we investigated the potential role of a deubiquitinase, ubiquitin-specific peptidase 25 (USP25), in MASLD. Analysis of mRNA profiling data showed that both human and mouse MASLD are associated with reduced expression of USP25 in hepatocytes. Usp25 deficiency exacerbated HFD-induced liver lipid accumulation and MASLD in mice. Rescue experiments with USP25 induction in hepatocytes protected mice against HFD-induced MASLD. Through comprehensive transcriptome sequence and pulldown-LC-MS/MS analysis, we identified that peroxisome proliferator-activated receptor α (PPARα) is involved in USP25's protective actions and may be the substrate protein of USP25. Cell-based experiments show that USP25 interacts with PPARα directly via its USP domain and the histidine at position 608 of USP25 exerts deubiquitination to increase protein stability by removing the K48 ubiquitin chain at PPARα's lysine at position 429. USP25 reduces palmitate (PA)-induced lipid accumulation in hepatocytes via increasing PPARα. Finally, we show that the protective effects of Usp25 induction are nullified in Ppara-deficient mice with HFD. In summary, this study presents a new USP25-PPARα axis in hepatocytes and highlights a novel function of USP25 in MASLD, suggesting that it may be targeted to combat the disease.

Lipids are a complex class of biomolecules with pivotal roles in the onset, progression, and maintenance of cancers. Lipids, derived from the tumor microenvironment (TME) or synthesized by cancer cells themselves, govern a large variety of pro-tumorigenic functions. In recent years, lipid metabolism and the reprogramming of liver cancer cells have received increasing attention, revealing that altered regulation of diverse lipid species, including triacylglycerols, phospholipids, sphingolipids, ceramides, fatty acids, and cholesterol, actively contributes to the initiation and progression of primary liver cancer. Lipid metabolic reprogramming also modifies the TME by influencing the recruitment, activation, and function of immune cells. Tumor-associated macrophages (TAM) are essential components of TME that sustain cancer growth, promoting invasion and mediating immune evasion. Macrophage polarization toward a tumor-supportive phenotype is associated with metabolic reprogramming. Indeed, lipid accumulation and enhanced fatty acid oxidation in TAM contribute to polarization to a M2 phenotype. In this review, we examine lipid metabolism in hepatocellular carcinoma and cholangiocarcinoma, focusing on TAM lipid metabolic reprogramming.

Metabolic reprogramming occurs alongside tumor development. As cancers advance from precancerous lesions to locally invasive tumors and then to metastatic tumors, metabolic patterns exhibit distinct changes, including mutations in metabolic enzymes and modifications in the activity of metabolic regulatory proteins. Alterations in metabolic patterns can influence tumor evolution, either establishing or alleviating metabolic burdens and facilitating cancer growth. To fully understand how metabolic reprogramming helps tumors grow and find the metabolic activities that are most useful for treating tumors, we need to have a deeper understanding of how metabolic patterns are controlled as tumors grow. Post-translational modifications (PTMs), a critical mechanism in the regulation of protein function, can influence protein activity, stability, and interactions in several ways. In tumor cells, PTMs-mediated metabolic reprogramming is a crucial mechanism for adapting to the challenging microenvironment and sustaining fast growth. This article will deeply explore the intricate regulatory mechanism of PTMs on metabolic reprogramming and its role in tumor progression, with the expectation of providing new theoretical basis and potential targets for tumor treatment.

The tumor environment of prostate cancer (PCa) tissues of high Gleason score has been proved to be more immune suppressive and has higher extracellular matrix (ECM) stiffness, but whether ECM mechanical stiffness is the cause of higher ability of invasiveness and immune escape of PCa with high Gleason score remains uncertain. In this study, we showed that higher polyacrylamide hydrogels (PAAG) stiffness resulted in the progression and immune escape of PCa via integrin β1/FAK/YAP axis. The translocation of YAP into cell nucleus to bind to TEAD2 promoted the transcriptional activation of USP8. NBR1 could be ubiquitinated, and then degraded, via interacting with P62/SQSTM1 and through autophagy-lysosome pathway. Increased expression of USP8 promoted the abundance of NBR1 via K63-linked de-ubiquitination and PD-L1 via K48-linked de-ubiquitination in response to high PAAG stiffness. NBR1-mediated selective autophagy accelerated the degradation of MHC-1 of PCa. The USP8 inhibitor presented a potential application value in sensitizing immunotherapy of PCa. Taken together, we identified a USP8-mediated de-ubiquitination mechanism that involves in the process of high PAAG stiffness-mediated high expression of PD-L1 and low expression of MHC-1 of PCa cells, which provided a rationale of immunotherapy sensitization of PCa via USP8 inhibition.

Peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors, have emerged as a key regulator of various biological processes, underscoring their relevance in the pathophysiology and treatment of numerous diseases. PPARs are primarily recognized for their critical role in lipid and glucose metabolism, which underpins their therapeutic applications in managing type 2 diabetes mellitus. Beyond metabolic disorders, they have gained attention for their involvement in immune modulation, making them potential targets for autoimmune-related inflammatory diseases. Furthermore, PPAR's ability to regulate proliferation, differentiation, and apoptosis has positioned them as promising candidates in oncology. Their anti-inflammatory and anti-fibrotic properties further highlight their potential in dermatological and cardiovascular conditions, where dysregulated inflammatory responses contribute to disease progression. Recent advancements have elucidated the molecular mechanisms of different PPAR isoforms, including their regulation of key signalling pathways such as NF-κB and MAPK, which are crucial in inflammation and cellular stress responses. Additionally, their interactions with co-factors and post-translational modifications further diversify their functional roles. The therapeutic potential of various PPAR agonists has been extensively explored, although challenges related to side effects and target specificity remain. This growing body of evidence underscores the significance of PPARs in understanding the molecular basis of diseases and advancing therapeutic interventions, paving way for targeted treatment approach across a wide spectrum of medical conditions. Here, we provide a comprehensive and detailed perspective of PPARs and their potential across different health conditions to advance our understanding, elucidate underlying mechanisms, and facilitate the development of potential treatment strategies.

Glioblastoma (GBM), the most common and aggressive primary brain tumour, is associated with poor prognosis, primarily due to its stem-like subpopulation, glioblastoma stem cells (GSCs). The deubiquitinase (DUB) family has attracted an increasing amount of attention due to its roles in GSC biology and tumour aggressiveness. In this study, we focused on ubiquitin-specific peptidase 18 (USP18), a member of the DUB family whose role in GBM is poorly understood. Through integrated bioinformatics analyses and experimental investigations using patient-derived samples, cell models, and animal models, we elucidated the role of USP18 in enhancing GSC stemness and promoting malignant behaviours. Our findings revealed that USP18 expression is significantly elevated in GBM and is correlated with a poor prognosis. Mechanistically, USP18 interacts with SRY-box transcription factor 9 (SOX9), stabilising its protein levels by cleaving K48-linked polyubiquitin chains. Additionally, we identified YY1 as a transcriptional regulator of USP18, increasing its expression in GBM cells. These findings reveal that USP18 is a potential therapeutic target and highlight the novel YY1/USP18/SOX9 signalling axis implicated in GBM progression.

Our study investigated the growth-related metabolic changes and microbial community dynamics during the early feeding stage of bullfrog (Lithobates catesbeiana) tadpoles. In this research, we examined the changes in fat accumulation patterns, as well as the levels of biochemical and enzymatic indicators and genes mRNA expression related to lipid metabolism across the endogenous, mixed, and exogenous nutritional stages of bullfrog tadpoles from a single mating pair. Simultaneously, we characterized the community structures of intestines, excreta, and water bodies during these stages using 16S rRNA high-throughput sequencing technology. Our findings reveal that fat accumulation in tadpole tissues gradually increases with the onset of feeding. Levels of alanine aminotransferase, aspartate aminotransferase, triacylglycerol, total cholesterol, non-esterified fatty acid, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol show a significant increase in exogenous nutritional stages. The mRNA levels of lipid synthesis-related genes and lipid degradation-related genes increased gradually with the changes of nutritional stage. Significant differences were observed in microbial community characteristics among intestines, excreta, and water bodies across nutritional stages. Specifically, gut microbiota exhibited a lower similarity to water body microbiota but a higher similarity to excreta microbiota. Notably, the phyla Firmicutes and Actinobacteriota, and the genus Cetobacterium within the gut microbiota, increased with nutritional changes. A Spearman correlation analysis highlighted a significant correlation between gut microbiota composition and lipid metabolism markers, particularly a strong positive association between Cetobacterium and lipid-related parameters. These insights provide a theoretical foundation for nutritional interventions aimed at enhancing tadpole growth and survival rates.

Metabolic dysfunction-associated steatotic liver disease (MASLD), closely associated with obesity, can progress to metabolic dysfunction-associated steatohepatitis when the liver undergoes overt inflammatory damage. A-kinase anchoring protein 1 (AKAP1) has been shown to control lipid accumulation in brown adipocytes. However, the role of AKAP1 signaling in hepatic lipid metabolism and MASLD remains poorly understood. Here, we showed that hepatocyte-specific AKAP1 deficiency exacerbated hepatic steatosis and steatohepatitis in male mice subjected to a high-fat diet and fast-food diet, respectively. Mechanistically, AKAP1 directly phosphorylated and inactivated glycerol-3-phosphate acyltransferase 1 (GPAT1) in a PKA-dependent manner, thus suppressing lysophosphatidic acid (LPA) production. Increased endogenous LPA in hepatocytes promoted hepatocellular triglyceride (TG) synthesis and initiated pronounced inflammatory response in Kupffer cells. Restoring hepatic AKAP1 or repressing LPA levels via GPAT1 knockdown alleviated MASLD exacerbation. Overall, AKAP1 plays a protective role against MASLD by inhibiting GPAT1 activity, highlighting the potential of targeting AKAP1/PKA/GPAT1 signalosome for MASLD therapy.

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.

Liver regeneration is critical for maintaining whole-body homeostasis, especially under exposure to deadly chemical toxins. Understanding the molecular mechanisms underlying liver repair is critical for the development of intervention strategies to treat liver diseases. In this study, ubiquitin-specific Proteases 42 (USP42) is identified as a novel deubiquitinases (DUB) of peroxisome proliferators-activated receptor γ (PPARγ) in hepatocytes. This DUB interacted, deubiquitinated, and stabilized PPARγ, and increased PPARγ targeted proliferative and antioxidative gene expressions, which protects the liver from carbon tetrachloride (CCL4) induced oxidative injury and promotes liver regeneration. In addition, fibroblast growth factor 2 (FGF2) initiated USP42 expression and enhanced the interaction between USP42 and PPARγ during the liver regeneration process. Moreover, the PPARγ full agonist, rosiglitazone (RSG), possesses the ability to further reinforce the USP42-PPARγ interplay, which enlightens to construct of an extracellular vesicle-based targeting strategy to activate the liver USP42-PPARγ axis and promote liver regeneration. In summary, the work uncovers the importance of USP42-PPARγ axis-mediated liver tissue homeostasis and provides a promising regimen to target this protein-protein interplay for liver regeneration.

Pediatric solid tumors represent a significant subset of childhood cancers, accounting for approximately 60% of new diagnoses. Despite advancements in therapeutic strategies, survival rates remain markedly disparate between high-income and resource-limited settings, underscoring the urgent need for novel and effective treatments. Lipid metabolic reprogramming is a fundamental hallmark of cancer, driving tumor progression, therapeutic resistance, and immune evasion through enhanced fatty acid uptake, increased de novo lipid synthesis, and activated fatty acid β-oxidation (FAO). Ubiquitination, a dynamic post-translational modification mediated by the ubiquitin-proteasome system (UPS), plays a crucial role in regulating lipid metabolism by modulating the stability and activity of key metabolic enzymes and transporters involved in cholesterol and fatty acid pathways. This review comprehensively examines the complex interplay between ubiquitination and lipid metabolic reprogramming in pediatric solid tumors. It delineates the mechanisms by which ubiquitination influences cholesterol biosynthesis, uptake, efflux, and fatty acid synthesis and oxidation, thereby facilitating tumor growth and survival. Furthermore, the review identifies potential UPS-mediated therapeutic targets and explores the feasibility of integrating ubiquitination-based strategies with existing treatments. By targeting the UPS to disrupt lipid metabolism pathways, novel therapeutic avenues may emerge to enhance treatment efficacy and overcome resistance in pediatric oncology. This synthesis of current knowledge aims to provide a foundation for the development of innovative, precision medicine approaches to improve clinical outcomes for children afflicted with solid tumors.

Atherosclerosis is a chronic inflammatory disease that strongly threatens human health, and macrophages play a pivotal role in its pathogenesis. Ubiquitin-specific peptidase 22 (USP22) is involved in the regulation of macrophage inflammation. However, its role in the atherosclerotic microenvironment remains unclear. In this study, we found that USP22 overexpression in macrophages alleviated atherosclerosis progression in ApoE-/- mice. In vitro, USP22 silencing enhanced macrophage inflammation and foam cell formation, and macrophage efferocytosis was significantly impaired. Mechanistically, USP22 bound to peroxisome proliferator-activated receptor γ (PPARγ) and inhibited its ubiquitination, thereby stabilizing PPARγ and promoting efferocytosis. In addition, intraperitoneal injection of the USP22 inhibitor USP22i-S02 exacerbated atherosclerosis in ApoE-/- mice. In summary, these findings indicate that USP22 may be a potential therapeutic target for the treatment of atherosclerosis.

Hepatocellular carcinoma (HCC) has a relatively poor prognosis and a high degree of malignancy. However, the therapeutic drugs are limited. In recent years, abnormal lipid metabolism and its important role in HCC has been reported, and emerging studies found that some formulae and active components of traditional Chinese medicine (TCM) can regulate abnormal lipid metabolism in HCC, showing their good application prospects. Therefore, this article summarizes the changes and the roles of lipid metabolites in HCC progression, and discusses the role of formulae and active components of TCM for the treatment of HCC based on their regulation on abnormal lipid metabolism. A deeper understanding of their relationship may help the precise use of these formulae and active components in HCC.

Liver cancer is a significant global health concern, with projections indicating that the incidence of morbidity may surpass one million cases by 2025. Hepatocellular carcinoma (HCC) is the predominant subtype of liver cancer, constituting approximately 90% of all liver cancer diagnoses. Infections caused by the hepatitis B virus (HBV) and hepatitis C virus (HCV) are recognized as primary risk factors for the development of HCC. However, non-alcoholic steatohepatitis (NASH), which is often linked to metabolic syndrome or diabetes, is increasingly being recognized as a prevalent risk factor in Western populations. Furthermore, HCC associated with NASH exhibits distinct molecular pathogenesis. Patients diagnosed with HCC have access to a range of therapeutic interventions, including liver transplantation, surgical resection, percutaneous ablation, radiation therapy, and transarterial and systemic therapies. Consequently, effective clinical decision-making requires a multidisciplinary approach to adapt individualized treatment plans based on the patient's tumor stage, liver function, and overall performance status. The approval of new first- and second-line pharmacological agents, along with the establishment of immune checkpoint inhibitor therapies as standard treatment modalities, has contributed to an improved prognosis for patients with HCC. Nevertheless, the optimal sequencing of these therapeutic agents remains to be elucidated, highlighting the urgent need for predictive biomarkers to inform treatment selections. Traditional Chinese Medicine (TCM) has demonstrated potential as a complementary and alternative therapeutic approach for liver cancer, warranting further investigation. This review aimed to examine the comprehensive treatment of HCC through the lens of TCM, informed by the current understanding of its epidemiology, diagnosis, and pathophysiology.

Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated fatty liver disease (MAFLD), is a leading cause of liver disease worldwide and can progress to cirrhosis and cancer. Despite its prevalence, the pathogenesis of MASH remains poorly understood, and there is only one U.S. Food and Drug Administration-approved treatment, highlighting the need for new therapeutic strategies. Peroxisome proliferator-activated receptor (PPAR)γ is activated in the liver under high-fat or obese conditions, promoting lipid storage and contributing to MASH progression. We found that USP28 expression is elevated in the livers of MAFLD/MASH patients. Through dietary induction, including a methionine-choline deficient (MCD) diet and a western diet (WD) combined with carbon tetrachloride (CCl4) injections, we established two severe mouse models of MASH to explore the role of USP28. Mechanistically, the hepatic deubiquitinase (DUB) USP28 directly binds to PPARγ, preventing its ubiquitination and subsequent degradation, thereby maintaining the integrity of the PPARγ signaling pathway. In the absence of Usp28 or if the DUB is inhibited, PPARγ is downregulated, and the PPAR signaling pathway is inhibited, enhancing cellular defenses against excess fat. Both genetic and pharmacological inactivation of Usp28 significantly reduced MASH severity induced by the MCD diet or WD-CCl4 regimen, as well as WD-CCl4-induced hepatocellular carcinoma in mice.

Pancreatic cancer stands as one of the most lethal malignancies, characterized by delayed diagnosis, high mortality rates, limited treatment efficacy, and poor prognosis. Disulfidptosis, a recently unveiled modality of cell demise induced by disulfide stress, has emerged as a critical player intricately associated with the onset and progression of various cancer types. It has emerged as a promising candidate biomarker for cancer diagnosis, prognosis assessment, and treatment strategies. In this study, we have effectively established a prognostic risk model for pancreatic cancer by incorporating multiple differentially expressed long non-coding RNAs (DElncRNAs) closely linked to disulfide-driven cell death. Our investigation delved into the nuanced relationship between the DElncRNA-based predictive model for disulfide-driven cell death and the therapeutic responses to anticancer agents. Our findings illuminate that the high-risk subgroup exhibits heightened susceptibility to the small molecule compound AZD1208, positioning it as a prospective therapeutic agent for pancreatic cancer. Finally, we have elucidated the underlying mechanistic potential of AZD1208 in ameliorating pancreatic cancer through its targeted inhibition of the peroxisome proliferator-activated receptor-γ (PPARG) protein, employing an array of comprehensive analytical methods, including molecular docking and molecular dynamics (MD) simulations. This study explores disulfidptosis-related genes, paving the way for the development of targeted therapies for pancreatic cancer and emphasizing their significance in the field of oncology. Furthermore, through computational biology approaches, the drug AZD1208 was identified as a potential treatment targeting the PPARG protein for pancreatic cancer. This discovery opens new avenues for exploring targets and screening drugs for pancreatic cancer.

Fatty acid metabolism is closely associated with hepatocellular carcinoma (HCC). Elucidating the molecules that influence fatty acid metabolism in HCC is important for developing precision therapies. However, uncovering the precise molecular mechanisms underlying changes in fatty acid metabolism in tumour cells is challenging. In this study, we aimed to determine the characteristics of fatty acid metabolism in HCC.

We employed organoid models, single-cell RNA sequencing, and spatial transcriptomics to identify key genes involved in tumour fatty acid metabolism. Metabolomics, proteomics, metabolic flux analysis, and transmission electron microscopy were utilized to evaluate this metabolic process. Tumour malignancy was characterized using multi-species models. Changes in the immune microenvironment were analysed by time-of-flight mass cytometry and multiplexed immunohistochemistry. Gene knockdown targeting the liver was achieved using lipid nanoparticles.

Eukaryotic translation initiation factor 3 subunit f (eIF3f) is upregulated in HCC tissues and is associated with poor prognosis. eIF3f directly interacted with and stabilised long chain acyl CoA synthetase 4 (ACSL4) through K48-linked deubiquitination, promoting fatty acid biosynthesis and malignancy. The increased fatty acid levels in the tumour microenvironment indirectly reduced CD8+ T-cell infiltration. In addition, phosphorylated eIF3f enhanced the interaction between eIF3f and ACSL4.

Targeting the eIF3f-ACSL4-fatty acid biosynthesis axis could decelerate the progression of HCC and enhance anti-programmed cell death-1 efficacy, implicating eIF3f as a potential target for precision therapy in HCC.

Fatty acid metabolism is closely associated with hepatocellular carcinoma (HCC), yet the underlying mechanisms involved remain unclear. Here, we found that eIF3f is upregulated in HCC and is associated with poor prognosis. eIF3f interacts with and stabilizes ACSL4, thereby promoting fatty acid biosynthesis. Additionally, increased fatty acid levels reduce CD8+ T-cell infiltration and activation. These findings are of significant importance for clinicians and researchers in the field of HCC treatment, as eIF3f inhibition combined with anti-PD-1 therapy significantly improved anti-tumour efficacy in a mouse model and could offer therapeutic benefits for patients. These findings have practical implications, as eIF3f could serve as a novel therapeutic target in HCC. However, further clinical studies are needed to confirm the efficacy of eIF3f targeting in human patients.

Protein quality control (PQC) plays a vital role in maintaining normal heart function, as cardiomyocytes are relatively sensitive to misfolded or damaged proteins, which tend to accumulate under pathological conditions. Ubiquitin-specific protease (USP) is the largest deubiquitinating enzyme family and a key component of the ubiquitin proteasome system (UPS), which is a non-lysosomal protein degradation machinery to mediate PQC in cells. USPs regulate the stability or activity of the target proteins that involve intracellular signaling, transcriptional control of inflammation, antioxidation, and cell growth. Recent studies demonstrate that the USPs can regulate fibrosis, lipid metabolism, glucose homeostasis, hypertrophic response, post-ischemic recovery and cell death such as apoptosis and ferroptosis in cardiomyocytes. Since myocardial cell loss is an important component of cardiomyopathy, therefore, these findings suggest that the UPSs play emerging roles in cardiomyopathy. This review briefly summarizes recent literature on the regulatory roles of USPs in the occurrence and development of cardiomyopathy, giving us new insights into the molecular mechanisms of USPs in different cardiomyopathy and potential preventive strategies for cardiomyopathy.

Cervical carcinoma (CC) poses significant health challenges, with its pathogenesis not fully understood. While ubiquitin specific peptidase 43 (USP43) is implicated in various cancers, its role in CC and regulation of the Hippo/Transcriptional Co-Activator With PDZ-Binding Motif (TAZ) pathway remain unexplored. This study examines USP43's impact on CC progression and its interaction with TAZ.

USP43 expression levels in CC tissues and cell lines were assessed using reverse transcription real-time polymerase chain reaction (RT-qPCR) and Western blot. The effects of USP43 silencing on cell proliferation, migration, and invasion were evaluated through cell counting Kit-8 (CCK-8), 5-ethynyl-2'deoxyuridine (EdU), colony formation, and transwell assays. Immunofluorescence staining and co-immunoprecipitation (Co-IP) assays were used to explore the interaction between USP43 and TAZ. Polyubiquitination assays were performed to evaluate ubiquitination and stability of TAZ, and cycloheximide (CHX) chase experiments determined the half-life of TAZ. In vivo studies using BALB/c nude mice examined the impact of USP43 knockdown on tumor growth and metastasis.

USP43 was overexpressed in CC tissues and cell lines. Silencing of USP43 reduced cell proliferation, migration, invasion, and the epithelial-mesenchymal transition (EMT) process. Co-IP and ubiquitination assays revealed that USP43 interacted with and stabilized TAZ by inhibiting TAZ ubiquitination. CHX chase experiments confirmed that USP43 prolonged TAZ protein stability. In vivo, USP43 knockdown led to reduced tumor growth and lung metastasis. Overexpression of TAZ reversed the inhibitory effects of USP43 silencing on CC cell proliferation, migration, invasion and EMT CONCLUSION: USP43 promotes CC cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) by activating the Hippo/TAZ pathway. These findings enhance our understanding of USP43's role in CC progression and highlight potential therapeutic targets for the treatment of CC.

Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver condition globally, lacks adequate and effective therapeutic remedies in clinical practice. Recent studies have increasingly highlighted the close connection between the ubiquitin-proteasome system (UPS) and the progression of MASLD. This relationship is crucial for understanding the disease's underlying mechanism. As a sophisticated process, the UPS govern protein stability and function, maintaining protein homeostasis, thus influencing a multitude of elements and biological events of eukaryotic cells. It comprises four enzyme families, namely, ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), ubiquitin-protein ligases (E3), and deubiquitinating enzymes (DUBs). This review aims to delve into the array of pathways and therapeutic targets implicated in the ubiquitination within the pathogenesis of MASLD. Therefore, this review unveils the role of ubiquitination in MASLD while spotlighting potential therapeutic targets within the context of this disease.

3-Hydroxyacyl-CoA dehydratase 2 (HACD2), an obesity-related gene involved in the elongation of long-chain fatty acids, is highly expressed in pancreatic cancer (PC) and is associated with patient prognosis. Interestingly, the study reveals that HACD2 mediated the proliferation of PC cells in a dehydratase-independent manner, affecting the downstream glycolytic pathway. Mechanistically, HACD2 promotes PC cells proliferation by binding to E3 ubiquitin-protein ligase parkin (PRKN) and enhancing pyruvate kinase PKM (PKM2) dissociation from PRKN, resulting in reduced ubiquitination of PKM2 and increased dimerization of PKM2, which subsequently promote c-Myc expression and tumor growth. Moreover, HACD2 overexpression-induced PC growth is mitigated by knockdown of PKM2 or overexpression of PRKN. Furthermore, the weight loss drug orlistat, which potentially binds to HACD2, disrupted the interaction between HACD2 and PRKN and further increased the ubiquitination of PKM2. Therefore, this study elucidates the mechanism by which the obesity-related gene HACD2 regulates PC cells proliferation through a noncanonical signaling pathway, which may provide a potential new target and strategy for the individualized clinical treatment of PC.

Doxorubicin(DOX) is an anthracycline chemotherapeutic drug used in the treatment of a wide range of tumors. However, the nephrotoxicity has limited the clinical application of DOX. Fatty acid-binding protein 4 (FABP4), a key adipokine mainly expressed in adipocytes, is strongly associated with kidney dysfunction and kidney disease. This study aims to investigate the role of FABP4 in DOX-induced nephrotoxicity. In vivo experiments, the mice were divided into 4 groups randomly: CON group, DOX group, 4T1 group, and 4T1 + DOX group respectively. DOX was given by intraperitoneal injection at a dose of 15 mg/kg. The kidney function indicators, the morphology and lipid deposition in renal tissues and the preliminary mechanism were assessed. In vitro experiment, HK-2 cell was used to detect DOX-induced kidney cell injury with or without BMS309403. DOX caused renal dysfunction in both DOX group and 4T1 + DOX group, with a more severe kidney injury in DOX group. DOX also induced kidney lipid deposition, glycerophospholipids metabolism dysfunction, apoptosis accompanied by increased FABP4 and decreased Peroxisome Proliferator Activated Receptor- γ (PPAR-γ) levels in the kidney tissues. The decreased cell viability, increased apoptotic ratio, elevated protein levels of apoptosis and the lipid deposition caused by DOX were all alleviated by BMS309403. FABP4 mediated DOX induced kidney damage in normal mice and tumor-bearing mice by lipid metabolism disorders and cell apoptosis. This study may enhance the clinical management of DOX-induced kidney injury and provide new therapeutic targets and preventive strategies for the clinical application of DOX.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer worldwide. Its primary risk factors are chronic liver diseases such as metabolic fatty liver disease, non-alcoholic steatohepatitis, and hepatitis B and C viral infections. These conditions contribute to a specific microenvironment in liver tumors which affects mitochondrial function. Mitochondria are energy producers in cells and are responsible for maintaining normal functions by controlling mitochondrial redox homeostasis, metabolism, bioenergetics, and cell death pathways. HCC involves abnormal mitochondrial functions, such as accumulation of reactive oxygen species, oxidative stress, hypoxia, impairment of the mitochondrial unfolded protein response, irregularities in mitochondrial dynamic fusion/fission mechanisms, and mitophagy. Cell death mechanisms, such as necroptosis, pyroptosis, ferroptosis, and cuproptosis, contribute to hepatocarcinogenesis and play a significant role in chemoresistance. The relationship between mitochondrial dynamics and HCC is thus noteworthy. In this review, we summarize the recent advances in mitochondrial alterations and signatures in HCC and attempt to elucidate its molecular biology. Here, we provide an overview of the mitochondrial processes involved in hepatocarcinogenesis and offer new insights into the molecular pathology of the disease. This may help guide future research focused on improving patient outcomes using innovative therapies.

Hepatocellular carcinoma (HCC) poses a substantial global health burden, with poor prognosis and high mortality rates. Dysregulated lipid metabolism has emerged as a critical driver of HCC progression. While mTORC1 signaling is known to promote lipid synthesis in HCC, the regulatory mechanisms governing mTORC1 remain largely unclear. Here, we demonstrate that mTORC1 inhibition significantly reduces lipogenesis in HCC and uncover a regulatory axis involving the transcription factor ATF3 and the leucine-arginine transporter SLC7A7. Transcriptomic analysis of HCC patients reveals an inverse correlation between ATF3 expression and lipid synthesis, a finding corroborated by experimental validation. Mechanistically, ATF3 suppresses mTORC1 signaling, thereby inhibiting lipid biosynthesis, with SLC7A7 identified as a key intermediary in this process. Specifically, ATF3 binds to the enhancer region of SLC7A7, driving its transcriptional activation and subsequently restraining mTORC1 activity. Functional assays in ATF3-overexpressing and -knockdown HCC cell lines further confirm ATF3's role as a tumor suppressor. Our study identifies a novel ATF3-SLC7A7-mTORC1 regulatory axis that attenuates lipogenesis and tumorigenesis in HCC, establishing a critical link between lipid metabolism and hepatocarcinogenesis. These findings offer new insights into potential therapeutic targets for the treatment of HCC.

Hepatocellular carcinoma (HCC) is a predominant cause of cancer-related mortality globally, noted for its propensity towards late-stage diagnosis and scarcity of effective treatment modalities. The process of metabolic reprogramming, with a specific emphasis on lipid metabolism, is instrumental in the progression of HCC. Nevertheless, the precise mechanisms through which lipid metabolism impacts HCC and its viability as a therapeutic target have yet to be fully elucidated. In the current investigation, single-cell RNA sequencing in conjunction with weighted gene co-expression network analysis (WGCNA) was utilized to delineate lipid metabolism-related genes correlated with the prognostic outcomes of hepatocellular carcinoma (HCC). Data procurement encompassed transcriptomic and clinical datasets from HCC patients, sourced from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repositories. Subsequent to this, consensus clustering analysis was implemented to stratify patients into distinct subgroups, contingent upon the expression patterns of lipid metabolism genes. Further analytical procedures involved functional enrichment analysis, evaluation of immune infiltration, and examination of the mutation landscape.PTGES3 was identified as a pivotal gene associated with lipid metabolism. Subsequent to its identification, cellular communication analysis was employed to assess the immunological attributes of PTGES3 within the tumor microenvironment. The functional role of PTGES3 was further corroborated through molecular docking simulations and in vitro experimental assays. We identified 27 genes associated with lipid metabolism, 18 of which exhibited significant correlation with overall survival in HCC patients. PTGES3 emerged as a central gene, demonstrating a robust association with immune cell infiltration and unfavorable prognosis. Cellular communication analysis revealed that PTGES3 exhibits the highest communication intensity with T cells, modulating the tumor microenvironment by potentiating the FN1/CD44 + MDK/NCL signaling pathway. Elevated expression of PTGES3 was linked to immunosuppressive cascades, diminished responsiveness to immunotherapy, and inferior overall survival outcomes. Molecular docking analysis indicated that etoposide, methotrexate, and doxorubicin could effectively bind to PTGES3. In vitro experiments confirmed that PTGES3 knockdown significantly impaired the proliferation, invasion, and migration of HCC cells. This study highlights the pivotal role of lipid metabolism in HCC progression and identifies PTGES3 as a potential prognostic biomarker and therapeutic target. These findings offer new insights into the development of targeted therapies for HCC, particularly in patients with high PTGES3 expression.

Recent studies have identified selective peroxisome proliferator-activated receptor γ (PPARγ) modulators, which synergistically engage in the inhibition mechanism of PPARγ-Ser273 phosphorylation, as a promising approach for developing safer and more effective antidiabetic drugs. Herein, we present the design, synthesis, and evaluation of a new class of organo-Se compounds, namely, benzothiaselenazole-1-oxides (BTSAs), acting as potent, reversible, and selective PPARγ covalent modulators. Notably, 2n, especially (R)-2n, displayed a high binding affinity and superior antidiabetic effects with diminished side effects. This is mainly because it can reversibly form a unique covalent bond with the Cys285 residue in PPARγ-LBD. Further mechanistic investigations revealed that it manifested such desired pharmacological profiles primarily by effectively suppressing PPARγ-Ser273 phosphorylation, enhancing glucose metabolism, and selectively upregulating the expression of insulin-sensitive genes. Collectively, our results suggest that (R)-2n holds promise as a lead compound for treating T2DM and also provides an innovative reversible covalent warhead reference for future covalent drug design.

Excessive lipid accumulation promotes the occurrence and progression of hepatocellular carcinoma (HCC), accompanied by high levels of fatty acid synthetase (FASN) and more active lipogenesis. Heat shock protein 90 (Hsp90) acts as a chaperone to maintain the stability and activity of the client proteins. Studies have revealed that Hsp90 regulates the lipid metabolism of HCC, but the effect of Hsp90 on FASN still remains unknown. This study aims to discover the mechanism of Hsp90 inhibition on lipid accumulation and investigate the different effects of Hsp90 N-terminal domain inhibitor STA9090 and C-terminal domain inhibitor novobiocin on FASN protein stability and transcription pathway in HCC. We found that HCC cells tended to store lipids, which could be disrupted by Hsp90 inhibitors in vivo and in vitro. High levels of Hsp90α and FASN in tumor tissue had correlation with poor prognosis of HCC patients, and Hsp90α interacted with FASN to maintain its protein stability. Furthermore, N-terminal domain of Hsp90α was essential for process of sterol regulatory element binding protein 1 to activate FASN transcription and Hsp90α prevented proteasomal degradation of liver X receptor α to upregulate FASN transcription via liver X receptor α/sterol regulatory element binding protein 1 axis. Our data reveal that Hsp90α promotes lipid accumulation by increasing the protein stability and FASN mRNA transcription, and can be alleviated by Hsp90 inhibitors, which provides a theoretical basis for Hsp90-targeted therapy on lipid metabolism in HCC.

Krüppel-like factors15 (KLF15) is a cancer suppressor in many cancers. However, its precise function in the development of hepatocellular carcinoma (HCC) remains unclear. Lipogenesis is necessary for the development of HCC. This research aims to investigate the role of KLF15 in the regulation of hepatic lipid production and HCC progression.

The binding relationships among genes were confirmed by ChIP, dual luciferase assays, and Co-IP. Lipogenesis was examined by oil red O staining. Triglyceride and cholesterol levels were measured through commercial kits. The effect of treatment on HCC cell viability, proliferation, migration, and invasion were assessed using CCK-8, clone formation, or transwell assays. A subcutaneous tumorigenic model was utilized to explore the effects of PDLIM2 in HCC in vivo.

KLF15 were downregulated in human HCC tissues. KLF15 overexpression reduced lipid droplet production, suppressed the expression of genes associated with lipogenesis, and promoted cell proliferation, migration, and invasion. KLF15 suppressed the NF-κB pathway through transcriptional activation of PDLIM2. PDLIM2 knockdown attenuated the effect of KLF15 overexpression on HCC. WSB2 degraded KLF15 through ubiquitination to promote HCC lipogenesis and development.

The ubiquitination degradation of KLF15 was mediated by WSB2, which led to transcriptional repression of PDLIM2 and further activation of the NF-κB pathway, ultimately promoting HCC lipogenesis and development.

IGFALS forms stable ternary complexes with insulin-like growth factors (IGF1 and IGF2) and IGF-binding proteins (IGFBP3 and IGFBP5), which prolong the half-lives of IGFs. Through immunohistochemical analysis of 90 pairs of clinical samples and bioinformatics analysis, we observed downregulation of IGFALS in hepatocellular carcinoma tissues, which was associated with poor patient prognosis. This prompted us to explore the specific molecular mechanism of action of IGFALS in the inhibition of hepatocellular carcinoma (HCC), which could be a potential new target for the treatment of HCC. In vitro experiments demonstrated that IGFALS inhibits the proliferation, invasion, and migration of hepatocellular carcinoma cells and suppresses epithelial-mesenchymal transition. Gene Set Enrichment Analysis (GSEA) revealed a positive correlation between IGFALS and the activation of the PPAR pathway. Western blotting, immunofluorescence colocalization, and co-immunoprecipitation assays confirmed that IGFALS binds to PPAR-γ and stabilizes it through deubiquitination. Inhibition of PPAR-γ reversed the anticancer effects of IGFALS. Furthermore, we showed that IGFALS/PPAR-γ upregulates the expression of HMGCS2. The tumor xenograft model supported our findings. Mass spectrometry analysis and co-immunoprecipitation assays indicated that IGFALS promotes the binding of PPAR-γ with USP9X, a deubiquitinating enzyme, thereby facilitating the deubiquitination of PPAR-γ. In conclusion, our findings demonstrate that IGFALS can suppress hepatocellular carcinoma via the PPAR-γ/HMGCS2 pathway.

Gastric cancer (GC) is an aggressive tumor type with an intricate pathogenesis and limited therapeutic options. Ubiquitin-specific protease 22 (USP22) is a protein implicated in cell proliferation, metastasis, and tumorigenesis. However, the regulatory mechanisms governing USP22 in GC are still not fully understood. In this study, we perform bioinformatics analysis to identify conserved miRNA recognition sites for miR-200b-5p within the 3'UTR of USP22. Validation via luciferase reporter assay confirms the transcriptional regulation of USP22 by miR-200b-5p. Overexpression of miR-200b-5p markedly inhibits the proliferation and migration of GC cells in vitro and suppresses tumor growth in vivo. Conversely, ectopic expression of USP22 reversed this effect by modulating the NF-κB signaling pathway. Additionally, qPCR analysis reveals an inverse correlation between the miR-200b-5p level and USP22 expression in GC. Collectively, our findings indicate that miR-200b-5p-mediated inhibition of USP22 attenuates cell proliferation by targeting the NF-κB signaling pathway in GC, suggesting that miR-200b-5p and USP22 could serve as potential diagnostic or therapeutic targets for gastric cancer and other related human diseases.

The highly heterogeneity of the tumor microenvironment (TME) in hepatocellular carcinoma (HCC) results in diverse clinical outcomes and therapeutic responses. This study aimed to investigate potential intercellular crosstalk and its impact on clinical outcomes and therapeutic responses.

Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST) and bulk RNA sequencing (RNA-seq) datasets were integrated to comprehensively analyze the intercellular interactions within the TME. Multiplex immunohistochemistry was conducted to validate the intercellular interactions. A machine learning-based integrative procedure was used in bulk RNA-seq datasets to generate a risk model to predict prognosis and therapeutic responses.

Survival analyses based on the bulk RNA-seq datasets revealed the negative impact of the naïve Cluster of Differentiation 4+ (CD4) T cells and Secreted Phosphoprotein 1+ (SPP1) macrophages on prognosis. Furthermore, their intricate intercellular crosstalk and spatial colocalization were also observed by scRNA-seq and ST analyses. Based on this crosstalk, a machine learning model, termed the naïve CD4+ T cell and SPP1+ macrophage prognostic score (TMPS), was established in the bulk-RNA seq datasets for prognostic prediction. The TMPS achieved C-index values of 0.785, 0.715, 0.692 and 0.857, respectively, across 4 independent cohorts. A low TMPS was associated with a significantly increased survival rates, improved response to immunotherapy and reduced infiltration of immunosuppressive cells, such as. regulatory T cells. Finally, 8 potential sensitive drugs and 6 potential targets were predicted for patients based on their TMPS.

The crosstalk between naïve CD4+ T cells and SPP1+ macrophages play a crucial role in the TME. TMPS can reflect this crosstalk and serve as a valuable tool for prognostic stratification and guiding clinical decision-making.

Metabolic dysregulation is emerging as a critical factor in tumorigenesis, and reprogramming of serine metabolism has been identified as an essential factor in the progression of hepatocellular carcinoma (HCC). Studies have shown that LKB1 deficiency can activate mTOR to upregulate the serine synthesis pathway (SSP) and promote tumor progression. Our team discovered that ubiquitin-specific protease 10 (USP10) can inhibit HCC proliferation through mTOR, but its relationship with SSP needs further investigation. The metabolite assays revealed a significant increase in serine content in HCC tissues. Through the LKB1/mTOR/activating transcription factor 4 (ATF4) axis, loss of USP10 may increase serine biosynthesis and promote the proliferation of HCC in vitro and in vivo. Furthermore, it was found that USP10 could activate LKB1 through deubiquitination. Analyzing clinical HCC tissues revealed a positive correlation between USP10 and LKB1. Additionally, those with high expression of USP10 in HCC tissues showed a better degree of tumor differentiation and longer overall survival time. Moreover, we found increased expression of both serine and its synthase in liver tumor tissues of USP10 liver-specific KO mice. Loss of USP10 inhibits the activity of LKB1, contributing to the stimulation of the mTOR/ATF4 axis and SSP and then promoting the proliferation of HCC. This work presents a novel approach for serine-targeted treatment in HCC.