ABSTRACTPromoting thermogenesis in adipose tissue to enhance energy expenditure is widely regarded as a promising strategy for obesity treatment. However, the development of effective thermogenic drugs remains challenging. Our screenings identified the natural compound Akebia Saponin D (ASD) as a potent brown fat thermogenesis activator in mice, showing effects through mitochondrial brown fat uncoupling protein 1 (UCP1)‐dependent pathways. ASD was found to significantly mitigate high‐fat diet‐induced obesity and enhance the mitochondrial quality of brown adipocytes to promote thermogenesis. Utilizing human protein microarrays, cellular thermal shift assay, and drug affinity responsive target stability, along with microscale thermophoresis and molecular docking analysis, we identified ubiquitin carboxyl‐terminal hydrolase 4 (USP4) as a direct target of ASD. ASD interacts with USP4 and promotes the deubiquitination of peroxisome proliferator‐activated receptor gamma, thus inhibiting its proteasomal degradation and enhancing the transcriptional activation of UCP1 in brown adipocytes. Additionally, USP4 knockdown was shown to attenuate brown fat thermogenesis induced by ASD. In summary, our findings demonstrate that ASD promotes brown fat thermogenesis by targeting USP4, highlighting its potential as a promising natural small molecule for obesity treatment.

ABSTRACTDysregulated copper homeostasis is implicated in inflammatory skin diseases such as psoriasis and atopic dermatitis (AD), but the role of cuproptosis remains poorly defined. This study aimed to elucidate the role and mechanism of cuproptosis in inflammatory skin diseases. Transcriptome analysis of patient lesions revealed significant alterations in cuproptosis‐related genes correlating with disease‐specific pathological features. These cuproptosis‐related gene expression signatures demonstrated strong clinical relevance to therapeutic efficacy in both psoriasis and AD cohorts. Functional validation using disease models showed that pharmacologically inhibiting cuproptosis with the copper chelator tetrathiomolybdate (TTM), or genetically knocking down the copper importer SLC31A1, effectively alleviated chronic skin inflammation and hallmark pathological changes induced by imiquimod (IMQ) or calcipotriol (MC903). Mechanistically, we uncovered that SLC31A1‐mediated cuproptosis promotes intracellular α‐ketoglutarate (α‐KG) accumulation, driving activation of the lysine demethylase KDM5B. Activated KDM5B specifically demethylates H3K4me3 marks at the promoter of the ferroptosis regulator ferritin heavy chain 1 (FTH1), suppressing its transcription and consequently sensitizing keratinocytes to ferroptotic cell death, thereby amplifying inflammatory tissue damage. Our findings establish a fundamental pathogenic SLC31A1/KDM5B/FTH1 molecular axis linking dysregulated copper metabolism and cuproptosis to ferroptosis execution in psoriasis and AD, providing significant mechanistic insights and pinpointing promising therapeutic targets for these refractory skin disorders.

ABSTRACTMyeloid‐derived suppressor cells (MDSCs) represent a significant immunosuppressive population within the tumor microenvironment of colorectal cancer (CRC). Their activity has been strongly associated with the reprogramming of cholesterol metabolism, although the underlying mechanisms remain unclear. To investigate this, we generated myeloid‐specific cholesterol 25‐hydroxylase (CH25H) knockdown mice and differentiated bone marrow cells from wild‐type (WT) or Ch25hf/f Lyz2Cre mice into MDSCs, subsequently treating them with 25‐hydroxycholesterol (25HC). Immune function was evaluated using flow cytometry, Western blotting, and real‐time polymerase chain reaction (PCR). Our findings indicated that CH25H and its metabolite 25HC were significantly upregulated in CRC‐associated MDSCs. The loss of CH25H impaired their immunosuppressive capacity by reducing arginase‐1 (ARG1) expression, an effect that was restored by 25HC supplementation. Mechanistically, 25HC suppressed the activation of the cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS–STING) pathway and the downstream tank‐binding kinase 1 (TBK1). TBK1 formed a complex with receptor‐interacting protein kinase 3 (RIPK3), thereby repressing ARG1 expression through phosphorylation‐dependent signaling. Collectively, these findings reveal a previously unrecognized CH25H–25HC–STING axis in MDSC‐mediated immune regulation and suggest that targeting cholesterol metabolism may provide a promising therapeutic strategy for CRC immunotherapy.

ABSTRACTF‐Box Protein 32 (FBXO32), a F‐box protein family member, exhibits oncogenic and tumor‐suppressive roles in various carcinomas. However, its function and underlying molecular mechanisms in hepatocellular carcinoma (HCC) are still unknown. We observed that FBXO32 was overexpressed in HCC tissues than normal tissues, which is pertaining to poor prognosis in HCC patients. Functional tests demonstrated that FBXO32 enhanced HCC cell proliferation, invasion, and metastasis, which was confirmed in vivo using mouse models. Proteomics‐based approaches and computational analyses reported a positive correlation between FBXO32 and PI3K–AKT pathway, identifying pleckstrin homology domain leucine‐rich repeat protein phosphatase 2 (PHLPP2) as an interacting protein. Mechanistically, DNA promoter hypomethylation elevated FBXO32 expression in HCC cells, promoting K48‐linked PHLPP2 polyubiquitination at the K592 and K942 sites through direct interactions. Notably, targeting FBXO32 significantly inhibited tumor growth in both an orthotopic HCC model and an organoid model derived from HCC patients. To sum up, this work emphasizes the part of FBXO32 in propelling HCC progression via facilitating PI3K–AKT pathway activation via PHLPP2 degradation.

ABSTRACTAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that lacks ideal models to comprehensively recapitulate its pathological features. TDP‐43 pathology, a hallmark of neurodegenerative diseases, plays a critical role in disease progression. Given the anatomical and physiological similarities between pig and human brains, large animal models offer a unique advantage in more accurately simulating patient‐specific disease characteristics. In this study, we rapidly established a TDP‐43‐induced neurodegenerative disease model in pigs through ear vein injection of the TDP‐43M337V virus. Disease progression was systematically evaluated using behavioral assessments and pathological analyses. This porcine model produced extremely severe motor dysfunction accompanied by significant muscle atrophy and fibrosis. Additionally, characteristic TDP‐43 pathological phenotypes were observed, including degeneration of spinal motor neurons and proliferation of glial cells in both the brain and spinal cord. Notably, TDP‐43M337V induction led to a significant upregulation of TMEM106B, SOD1, and APOE4 levels. This TDP‐43 porcine model recapitulates multiple key features of ALS and serves as a valuable complement to existing animal models, providing a robust platform for investigating TDP‐43‐related pathogenic mechanisms of TDP‐43 and developing effective therapeutics.

ABSTRACTCancer metabolic reprogramming is a fundamental hallmark that enables tumor cells to sustain their malignant behaviors. Beyond its role in supporting growth, invasion, and migration, metabolic rewiring actively contributes to anticancer drug resistance. Cancer cells not only reshape their own metabolism but also engage in aberrant metabolic crosstalk with nonmalignant components within the tumor microenvironment (TME). These metabolic alterations create multiple barriers to the efficacy of drug therapies, including chemotherapy, targeted therapy, and immunotherapy. Despite growing evidence, an integrated understanding of how metabolic reprogramming contributes to the development of drug resistance and how it may be therapeutically targeted to overcome the resistance remains incomplete. This review summarizes recent progresses in tumor‐intrinsic and TME‐associated metabolic alterations that contribute to drug resistance by sustaining metabolic needs and modulating nonmetabolic processes and explores the upstream regulatory mechanisms driving these changes, focusing particularly on glucose, lipid, and amino acid metabolism. We also discuss the current advances in the integration of small molecule inhibitors targeting cancer metabolism to address drug resistance. By consolidating mechanistic insights and therapeutic opportunities, this review highlights metabolic reprogramming as a promising intervention point to overcome anticancer drug resistance.

The activation of nucleotide oligomerization domain‐like receptor (NLR) family, pyrin domain‐containing protein 3 (NLRP3) inflammasome is implicated in the pathogenesis of various inflammatory diseases. The natural product oridonin possesses a novel mechanism for NLRP3 inhibition and a unique binding mode with NLRP3, but its poor anti‐inflammatory activity limits further application. After virtual screening of diverse natural product libraries, dehydrocostus lactone (DCL) was considered as a potential NLRP3 inhibitor. DCL effectively inhibited caspase‐1 cleavage and release of IL‐1β in mouse and human macrophages at an extremely low concentration of 10 nM, comparable to MCC950. Mechanistically, our study assigned DCL a novel role in disrupting NLRP3 inflammasome assembly and ASC oligomerization. Excluding the influence on potassium/chloride ion efflux, calcium ion influx, and production of mitochondrial ROS, DCL formed a covalent bond with cysteine 280 in NACHT domain of NLRP3, thereby inhibiting the interaction between NLRP3 and NEK7. Furthermore, DCL exhibited protective effects in mouse models of NLRP3 inflammasome‐mediated diseases, including dextran sulfate sodium‐induced colitis, 2,4,6‐trinitrobenzenesulfonic acid‐induced Crohn's disease, LPS‐induced septic shock, and monosodium urate‐induced peritonitis. Our findings identify NLRP3 as the direct target of DCL, positioning DCL as a promising lead compound for treatment of NLRP3 inflammasome‐related diseases.

ABSTRACTRadiation therapy is a fundamental component of cancer treatment, benefiting 50%–70% of patients by selectively targeting malignant tissues. However, radioresistance remains a significant challenge, often driven by epithelial–mesenchymal transition (EMT). EMT increases cancer invasiveness and metastasis by upregulating mesenchymal markers, including vimentin and N‐cadherin, and downregulating epithelial markers, such as E‐cadherin. EMT under radiation involves principal signaling pathways, including TGF‐β, Wnt/β‐catenin, Notch, and ERK, which regulate EMT through transcription factors such as Snail, Slug, Twist, and Zeb1/2. These alterations drive cytoskeletal reorganization, decrease cell–cell adhesion, and enhance extracellular matrix degradation via integrins, MMP‐2, and MMP‐9. We also explored how growth hormones, inflammatory cytokines, and hypoxia in the tumor microenvironment affect radiation‐induced EMT. Targeting EMT pathways with monoclonal antibodies and small‐molecule inhibitors of signaling pathways may help overcome radioresistance. However, due to the dual role of EMT in cancer progression and tissue regeneration, precise treatment strategies are essential. There is a lack of comprehensive multi‐omics studies that provide insights into postradiation EMT progression. This review examines how radiation induces EMT and its impact on metastasis and immune responses while also proposing therapeutic approaches. Integrating EMT‐targeting strategies with existing cancer treatments could enhance the effectiveness of radiotherapy and improve patient outcomes.