Liquid biopsy is a promising, noninvasive approach for cancer detection, but current methods often trade off accuracy, operability, and cost. To address these limitations, we introduce an artificial perception system (APS) for liquid biopsy that combines a structurally defined DNA-carbon nanotube sensor array with machine learning (ML) models. The array produces multichannel fluorescence fingerprints from serum, which are decoded by ML models to classify disease state. In a total of 253 serum samples spanning liver, lung, and ovarian cancers and noncancer controls, the APS achieved mean sensitivity of 89% and specificity of 96%. Notably, early-stage lung cancer was detected with 92% sensitivity and 95% specificity at an estimated cost of ∼$4 USD per test. Insights from SHAP analysis and Mantel test revealed the detection mechanisms of APS, supporting biological plausibility and clinical translation. These results highlight a path toward accurate, scalable, and affordable multicancer detection and early cancer screening.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective treatment options, and paclitaxel resistance remains a major clinical challenge. This study investigated the role of VASN in mediating paclitaxel resistance in TNBC by integrating transcriptomic and single-cell RNA sequencing data from public databases and clinical samples. Using paclitaxel-resistant TNBC cell lines (MDA-MB-231R and CAL-51R) and xenograft models, we revealed that VASN was significantly upregulated in resistant TNBC cells and tissues, correlating with poor prognosis. Mechanistically, CEBPB directly bound to the VASN promoter to activate its transcription, and VASN interacted with IGF2BP3 via its LRR domain, recruiting USP10 to deubiquitinate and stabilize IGF2BP3 by suppressing K48-linked polyubiquitination. Stabilized IGF2BP3 enhanced ABCB1 expression through m⁶A-dependent mRNA stabilization, activating the PI3K/AKT pathway and driving paclitaxel resistance. Genetic or pharmacological inhibition of VASN resensitized resistant cells to paclitaxel, and computational drug screening identified Trametinib as a candidate to downregulate VASN. Trametinib synergized with paclitaxel to effectively suppress tumor growth without obvious toxicity in resistant models. In summary, we uncovered a new CEBPB-VASN/IGF2BP3/USP10-ABCB1 axis responsible for paclitaxel resistance in TNBC. Targeting VASN with Trametinib in combination with paclitaxel represents a promising therapeutic strategy to overcome chemoresistance, offering a rationale for precision medicine in resistant TNBC.

Oral squamous cell carcinoma (OSCC) is associated with aggressive clinical behavior and poor outcomes. In this study, we investigated the anticancer efficacy and underlying mechanisms of Stellettin B, an isomalabaricane triterpene isolated from the marine sponge Jaspis stellifera, in OSCC cells. Our results demonstrate that Stellettin B significantly inhibited the proliferation of HSC-3 and OC-2 cells while sparing normal oral keratinocytes. Mechanistically, Stellettin B triggers a predominantly caspase-independent apoptotic program, evidenced by the pronounced mitochondrial-to-nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) following DNA damage, whereas classical caspase activation functions as a dispensable, secondary event. Furthermore, Stellettin B suppressed migration and invasion by reversing epithelial-mesenchymal transition (EMT), characterized by E-cadherin upregulation and downregulation of Vimentin, Snail, Slug, and β-catenin. Transcriptomic profiling further revealed significant suppression of mTORC1 signaling and EDIL3 expression. In conclusion, these findings demonstrate that Stellettin B exerts multimodal antitumor activity in OSCC and highlight its therapeutic potential as a marine-derived anticancer agent.

Programmed death-ligand 1 (PD-L1) has long been characterized as a membrane-bound immune checkpoint ligand that suppresses antitumor immunity through engagement with PD-1 on T cells. This canonical understanding has underpinned the development of therapeutic antibodies that have revolutionized cancer treatment. However, PD-1/PD-L1 immunotherapy still has limitations such as poor response rates and post-treatment resistance. Notably, emerging evidence reveals that the roles of PD-L1 extend beyond its membrane-bound form, with substantial pools residing in the cytoplasm, nucleus, organelles, and extracellular vesicles. These intracellular PD-L1 populations perform distinct, often immune-independent functions including transcriptional regulation, mRNA stability control, DNA damage response modulation, and metabolic reprogramming. This review examines the subcellular localization of PD-L1, the mechanisms governing its trafficking and compartmentalization, its compartment-specific biological functions, and the corresponding clinical significance. Understanding the full spectrum of PD-L1 biology is essential for developing more effective immunotherapeutic approaches and promoting individualized treatment strategies.

Lipid metabolic reprogramming plays a crucial role in modulating tumor responses to radiotherapy by influencing radiation-induced oxidative damage, membrane repair, ferroptosis, energy stress, and immune regulation. Within the context of ionizing radiation, lipid pathways of particular significance include iron-dependent lipid peroxidation and ferroptosis, cholesterol and phospholipid remodeling that impacts membrane integrity and lipid rafts, lipid droplet-mediated buffering of metabolic stress, fatty acid oxidation-dependent energy supply, and sphingolipid-regulated apoptosis. This review delineates pre-existing tumor lipid programs from IR-induced adaptive responses, highlighting that their contributions to radiosensitivity or radioresistance are contingent upon tumor lineage, genetic background, microenvironmental conditions, and treatment context. The coupling of cancer cells with their microenvironment through lipid interactions, encompassing intercellular lipid transfer, nutrient competition, paracrine lipid mediators, and exosome-mediated signaling, is identified as a central component of radioresistance. In conclusion, therapeutic opportunities are evaluated based on their translational maturity, encompassing a spectrum from mechanistic concepts and preclinical radiosensitization strategies to approaches with emerging clinical significance. This synthesis, focused on radiotherapy, seeks to elucidate how lipid vulnerabilities can be strategically and judiciously exploited to enhance radiation outcomes.

Licoricidin (LCD), a natural isoflavonoid compound extracted from Glycyrrhiza species, has been extensively demonstrated to possess diverse biological activities, including anti-inflammatory and potent anti-cancer effects. However, the precise mechanism underlying LCD action against hepatocellular carcinoma (HCC) remains unclear, particularly regarding its regulation of cell death. In this study, we comprehensively explored the effects of LCD on HCC cells in vitro and investigated its role and mechanism of action in the induction of PANoptosis. Our results reveal that LCD exhibited potent anti-HCC activities by decreasing cell viability and significantly inhibiting clonogenic survival in HCC cell lines. Our results demonstrate that LCD triggered a substantial accumulation of reactive oxygen species and induced depolarization of the mitochondrial membrane, leading to profound mitochondrial dysfunction. We further confirmed that LCD activated a comprehensive PANoptosis program by synchronously upregulating the expression of apoptotic proteins (Bax, c-CASP3, and c-PARP1), pyroptotic proteins (c-CASP 1 and c-GSDMD), and the phosphorylation of necroptotic executioners (p-MLKL and p-RIPK1). Treatment with the ROS inhibitor (NAC), apoptosis inhibitor (ZVAD), or necroptosis inhibitor (Nec-1) significantly reduced the expression of PANoptosis-related proteins in LCD-treated cells. Furthermore, molecular docking simulations and cellular thermal shift assay (CETSA) assay confirmed the direct and stable binding of LCD to PANoptosis-related proteins. In summary, we show for the first time that LCD exerts favorable anti-HCC activities via the induction of PANoptosis through a ROS-dependent mechanism and potntial direct modulation of core executive proteins. This multi-target action suggests that LCD could be a novel candidate for the management of hepatocellular carcinoma.

Triple-negative breast cancer (TNBC) primarily relies on traditional adjuvant chemotherapy and radiotherapy, which have significant side effects and are prone to drug resistance. Poly ADP-ribose polymerase inhibitor (PARPi) has been approved for TNBC patients with BRCA mutation, but some BRCA wild-type patients with homologous recombination deficiencies are also sensitive to PARPi. Therefore, it is important to identify potential molecules that influence PARPi sensitivity in BRCA wild-type TNBC and to explore their specific mechanisms. Through CRISPR-cas9 loss-of-function screening, the lncRNA MTUS2-AS1 was identified to be significantly correlated with PARPi sensitivity in BRCA wild-type TNBC cells. In vitro and in vivo experiments were performed to investigate its function and underlying mechanism. We found that MTUS2-AS1 knockdown suppressed DNA damage repair and enhanced the anticancer effects of PARPi in BRCA-wild TNBC cells. Mechanistically, MTUS2-AS1 upregulates DDX5 protein expression by maintaining its stability, thereby promoting R-loop resolution, and suppressing DNA damage. Knocking down MTUS2-AS1 accelerated DDX5 protein degradation, reduced DDX5 protein expression, inhibitd R-loop resolution, promoted DNA damage, and ultimately enhanced the PARPi sensitivity in TNBC cells. Our study provided new insights into exploring the key molecules and mechanisms influencing the sensitivity of PARPi treatment and had great significance for screening benefit population and expanding the indications of PARPi treatment.

Pazopanib, a first-line tyrosine kinase inhibitor for advanced renal cell carcinoma (RCC), faces significant clinical limitations due to acquired resistance. In this study, we reveal a novel mechanism underlying pazopanib resistance in RCC, driven by a senescence-like phenotype without cell-cycle arrest. Transcriptomic profiling identified ALYREF as a key upregulated m⁵C reader in pazopanib resistant cells. Mechanistically, ALYREF stabilizes CCNA1 mRNA via m⁵C modification, promoting Cyclin A1 expression. The Cyclin A1-CDK2 complex phosphorylates p21 at Thr-57, inducing its cytoplasmic translocation and abrogating its inhibitory effect on cell cycle progression, thereby facilitating G1-S transition. Our findings uncover a critical ALYREF-Cyclin A1-p21 axis in RCC and suggest that targeting this pathway may provide novel therapeutic strategies to overcome pazopanib resistance.

Protein S-palmitoylation, the reversible thioesterification of cysteine side chains, is emerging as a druggable post-translational modification that couples membrane topology to oncogenic, metabolic, immune, and epigenetic networks in cancer. ZDHHC palmitoyltransferases and depalmitoylating enzymes, including acyl-protein thioesterases and palmitoyl-protein thioesterase 1, constitute a dynamic circuitry that governs the localization, stability, and signaling competence of key regulators of tumor growth, metabolic adaptation, and immune phenotype. Here, we synthesize recent structural and chemical biology advances that clarify how human ZDHHC enzymes achieve acyl-chain recognition and substrate engagement. Structural studies show that these enzymes adopt a four-transmembrane, "tent-like" fold, in which the helices create a membrane-embedded cavity for acyl-chain accommodation. We also discuss how ankyrin-repeat domains and accessory partners shape substrate recruitment and subcellular localization, and we highlight emerging high-throughput platforms that enable quantitative profiling of isoform- and site-selective modulators. We then discuss how ZDHHC-substrate circuits rewire canonical growth-factor signaling and epithelial-mesenchymal transition programs, metabolic and ferroptotic control nodes, innate immune sensing, and chromatin-linked regulation. These convergent mechanisms position ZDHHC-mediated S-palmitoylation as a context-dependent regulator of tumor progression, therapy response, ferroptosis sensitivity, and immune phenotype. Finally, we outline a translational framework encompassing clinical-stage PPT1 inhibitors, selective ABHD17 blockade, emerging ZDHHC modulators, substrate-competitive strategies targeting checkpoint palmitoylation, and selected comparator approaches affecting Wnt and Hedgehog ligand lipidation. Current evidence positions ZDHHC-mediated S-palmitoylation as a regulatory layer with potential biomarker and therapeutic relevance; however, not all reported ZDHHC-substrate associations carry equivalent evidentiary weight. Mechanisms supported by convergent site-directed, genetic, biochemical, functional, and in vivo evidence should be distinguished from associations inferred mainly from expression profiling, overexpression systems, single-model observations, or broad pharmacological perturbation. Clinical translation remains preliminary and is constrained by isoform selectivity, substrate redundancy, incomplete pharmacodynamic read-outs, and the absence of validated biomarker-guided patient stratification.

Over 70% of patients experience bone metastases, a serious and crippling side effect of breast cancer that increases morbidity. There is an urgent need for innovative therapies because current therapeutic options, including systemic and local treatments, are limited by significant side effects and poor survival improvements. Helminthostachys zeylanica is the source of Ugonin L, a naturally occurring substance with established anti-inflammatory properties. However, its role in breast cancer-associated osteolytic bone metastasis remains elusive. Here, we demonstrate that Ugonin L suppresses epithelial-mesenchymal transition (EMT), migration, and invasion of breast cancer cells. We identify Netrin-1 (NTN-1) as a critical mediator of Ugonin L-induced inhibition of EMT and cell motility. Clinical data analyses revealed that elevated NTN-1 expression is significantly linked with disease progression, poor overall survival, and bone metastasis in breast cancer patients. Mechanistically, Ugonin L inhibits NTN-1-dependent EMT and motility by suppressing the canonical Wnt/β-catenin signaling pathway. Furthermore, Ugonin L attenuates breast cancer-promoted osteoclast differentiation by downregulating NTN-1 expression. Importantly, Ugonin L markedly suppresses breast cancer-induced osteolytic bone lesions in vivo. Collectively, these results position Ugonin L as a promising therapeutic candidate for the prevention and remedy of osteolytic bone metastasis in breast cancer.