Lipid metabolism reprogramming is a hallmark metabolic feature in the pathogenesis and progression of colorectal cancer(CRC), primarily involved in the aberrant activation of de novo lipogenesis(DNL), disruption of cholesterol homeostasis, enhancement of fatty acid oxidation(FAO), and resistance to ferroptosis. All of these pathological processes mediate malignant progression and multidrug resistance of tumors. According to TCM, the pathological foundation of CRC lies in the interlocking of "dampness, heat, stasis, and deficiency", which exhibits an intrinsic biological consistency with ectopic lipid accumulation, metabolic pathway perturbations, and the imbalance of microenvironmental homeostasis. This article systematically reviewed the molecular regulatory networks of lipid metabolism reprogramming in CRC, emphasizing the molecular mechanisms by which active components of TCM intervene in lipid metabolism homeostasis by modulating core targets such as sterol regulatory element-binding proteins(SREBPs), glutathione peroxidase 4(GPX4), solute carrier family 7 member 11(SLC7A11), and carnitine palmitoyltransferase 1(CPT1). Pharmacological studies demonstrate that active ingredients, including berberine, tanshinone Ⅱ_A, ginsenosides, curcumin, and hesperetin, elucidate the molecular scientific connotations of therapeutic principles, such as "clearing heat, drying dampness, promoting blood circulation, removing toxic substances, strengthening body resistance to consolidate the constitution, and disinhibiting dampness to transform phlegm", by intervening in lipid synthesis, ferroptosis, energy metabolism, and inflammatory signaling pathways. Furthermore, the clinical application potential of active components of TCM in reversing chemotherapy resistance, synergizing with immunotherapy, and the chemoprevention of adenomas is systematically evaluated. By providing an in-depth analysis of the biological correlations between TCM syndrome theory and lipid metabolism regulation, this review aims to offer a pharmacological basis for the development of TCM candidates targeting metabolic remodeling and for the optimization of diagnostic and therapeutic protocols of integrated Chinese and western medicine.

Hepatocellular carcinoma, hereinafter referred to as liver cancer, is a prevalent malignant tumor of the digestive system in China, with persistently high incidence and mortality rates. Currently, clinical management of liver cancer faces significant challenges, including elevated postoperative recurrence rates and drug resistance in advanced-stage patients, underscoring an urgent demand for the development of novel preventive and therapeutic strategies and agents. TCM with its distinct advantages of multi-efficacy, multi-targeted action, and multi-mechanism effect, has long been employed in anti-hepatocellular carcinoma therapy. As the limitations of western medicine in liver cancer treatment become increasingly prominent, active components of TCM monomers and their compound formulas have garnered extensive attention. A growing body of research indicates that flavonoids from TCM possess notable anti-hepatocellular carcinoma effects. Quercetin, a natural flavonoid, is widely distributed in various TCM herbs, including Artemisiae Scopariae Herba, Ploygoni Cuspidati Rhizoma et Radlx, Moutan Cortex, Plantaginis Semen, Spreading Hedyotis Herba, Eucommiae Folium, Ginkgo Folium, and Mori Folium. Quercetin exhibits unique advantages and promising application prospects due to its diverse pharmacological activities, such as antioxidant, anti-inflammatory, immunomodulatory, hepatoprotective, and anti-tumor effects. Focusing on the key molecular networks and the tumor microenvironment involved in hepatocarcinogenesis and progression, this review comprehensively synthesized the mechanisms underlying the anti-hepatocellular carcinoma effects of quercetin, encompassing its regulation of hepatocellular carcinoma cell proliferation and apoptosis, modulation of signaling pathways, inhibition of cell migration and invasion, as well as its regulatory roles in tumor metabolism, the microenvironment, and drug resistance. Additionally, the progress in the clinical application of quercetin was systematically summarized. This review aims to provide a theoretical foundation for the utilization of quercetin in the clinical treatment of liver cancer, facilitate the optimization of its therapeutic regimens, and offer a relevant basis for future in-depth research and clinical translation.

This study investigated the effect of gypenosides(GPs) on anoikis resistance(AR) in human triple-negative breast cancer(TNBC) MDA-MB-231 cells and explored the underlying mechanism involving the transforming growth factor β1(TGF-β1)/forkhead box protein P3(Foxp3)/retinoic acid-related orphan receptor γt(RORγt) signaling axis. An anoikis model was established using poly-HEMA coated plates, and cells were divided into normal adherent, anoikis model, GPs(100 μg·mL~(-1)), TGF-β1 inhibitor(LY, 10 μmol·L~(-1)), and GPs + LY groups. Cell viability, apoptosis, invasion and migration were assessed by CCK-8 assay, flow cytometry with AnnexinV-FITC/PI staining, and Transwell assay, respectively. The mRNA and protein expression levels of TGF-β1, Foxp3, RORγt, B-cell Lymphoma 2(Bcl-2), Bcl-2 associated X protein(Bax), cysteine aspartic acid specific protease-3(caspase-3), and Smad2/3 phosphorylation levels were measured by quantitative real-time PCR(qRT-PCR) and Western blot. Nuclear localization of Foxp3 and RORγt was examined by immunofluorescence staining. A breast cancer bone metastasis model was established in nude mice by tail vein injection. After intervention, the circulating tumor cells(CTCs) in peripheral blood and the formation of bone metastasis foci were evaluated. The mRNA and protein expression levels of TGF-β1, Foxp3, RORγt in bone metastasis foci of each nude mouse breast cancer bone metastasis model were detected using qRT-PCR and Western blot. In vitro experimental results showed that GPs inhibited the viability of human breast cancer MDA-MB-231 cells, promoted apoptosis, and reduced the number of invasive and migratory cells. GPs downregulated the mRNA and protein expression levels of TGF-β1, Foxp3, and Bcl-2, upregulated the expression levels of RORγt, Bax, and caspase-3, and inhibited Smad2/3 phosphorylation. Furthermore, GPs decreased Foxp3 nuclear accumulation and enhanced RORγt nuclear localization, and exhibited synergistic effects with LY. In vivo experimental results indicated that GPs reduced the number of CTCs in peripheral blood and the number of bone metastases in nude mice. The changes in key mRNA and protein expression levels of the TGF-β1/Foxp3/RORγt signaling axis in bone tissue were consistent with those observed in in vitro experiments. In summary, GPs inhibit the TGF-β1/Smad signaling axis, downregulate Foxp3 expression and its nuclear localization, thereby relieving its negative regulation on RORγt. This leads to upregulation of pro-apoptotic proteins Bax and caspase-3, downregulation of anti-apoptotic protein Bcl-2, disruption of anoikis resistance, and reduction of metastatic potential in MDA-MB-231 cells. These findings reveal that the TGF-β1/Foxp3/RORγt signaling axis is a key target of GPs against metastatic triple-negative breast cancer(TNBC), providing new experimental evidence and clinical strategies for natural product-based therapy in TNBC.

This study aimed to explore the mechanism by which psoralen regulates the neurogenic gene homologous protein(Notch)/zinc-finger transcription factors(Snail) pathway to inhibit liver metastasis of colorectal cancer. SW480 cells were allocated into a blank control group, low-, medium-, and high-concentration psoralen groups, and a high-concentration psoralen + Notch activator(Jagged1) group. The cell migration, invasion, mRNA levels of matrix metalloproteinase(MMP)-2, MMP-9, epithelial cadherin(E-cadherin), neural cadherin(N-cadherin), and protein levels of Notch1 and Snail were measured. Mice were assigned into a normal group, a model group, low-, medium-, and high-dose psoralen groups, a 5-fluorouracil(5-FU) group, and a high-dose psoralen + Jagged1 group, with 12 mice in each group. Liver metastasis in mice was examined via in vivo imaging. The liver weight, number of surface nodules, liver tissue pathology, and the above mRNA and protein levels were examined. The safety of psoralen was evaluated. The results showed that compared with the blank control group, psoralen decreased the scratch healing rate, number of invasive cells, mRNA levels of MMP-2, MMP-9, and N-cadherin, and protein levels of Notch1 and Snail, while increasing the mRNA level of E-cadherin in a concentration-dependent manner. In animal experiments, compared with the model group, the low-, medium-, and high-dose psoralen groups and the 5-FU group showed alleviated pathological damage in the liver tissue, reduced region of interest(ROI) values of liver fluorescence area, liver weight, number of surface nodules, mRNA levels of MMP-2, MMP-9, and N-cadherin, and protein levels of Notch1 and Snail but increased mRNA level of E-cadherin. Moreover, psoralen functioned in a dose-dependent manner. Jagged1 reversed the inhibitory effect of high-dose psoralen on liver metastasis of colorectal cancer in mice. Psoralen did not cause significant toxicity to hematopoietic, liver, or kidney functions at the tested doses. In conclusion, psoralen may inhibit liver metastasis of colorectal cancer by suppressing the Notch/Snail pathway.

The incidence and mortality of malignant tumors remain persistently high, while current clinical chemotherapeutic agents are often limited by significant drug resistance and adverse reactions. Consequently, small-molecule compounds derived from traditional Chinese medicine(TCM) have emerged as a focus in anti-tumor research owing to their advantages of multi-targeting action and low toxicity. As the core active component of Glycyrrhiza uralensis, glycyrrhizic acid(GA) is an oleanane-type pentacyclic triterpenoid saponin, constituting 5%-11% of the total content of G. uralensis. Its anti-tumor activity has been validated across various tumor systems, with mechanisms of action encompassing key processes such as cell cycle arrest, induction of tumor cell apoptosis, inhibition of tumor angiogenesis, blockage of invasion and metastasis, regulation of the tumor immune microenvironment(TIME), and alleviation of chronic inflammation. In terms of its therapeutic value, the combination of glycyrrhizic acid with other agents, such as tanshinone Ⅱ_A(Chinese medicine) or cisplatin(conventional chemotherapy) can achieve enhanced efficacy, reduced toxicity, targeted delivery, and reversal of drug resistance. This positions GA as possessing dual values, functioning both as a therapeutic agent and as a drug delivery carrier. This review systematically summarized the anti-tumor pharmacological activities, mechanisms, combined medication potential, and safety profiles of GA. It elaborated on the network mechanism of core regulatory hubs, analyzed the limitations of current research, and proposed targeted strategies for clinical translation. This work aims to provide a reference for the transition of GA from fundamental research to clinical application, while also offering a paradigm for the development of anti-tumor small-molecule compounds from TCM.

The programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1) signaling pathway is a key mechanism underlying tumor immune escape. It suppresses anti-tumor immune responses through various mechanisms, including T-cell exhaustion, expanding regulatory T cells(Tregs), promoting M2 macrophage polarization, inhibiting natural killer(NK) cell function, and disrupting the balance of glycolysis/fatty acid oxidation metabolism. Immune checkpoint inhibitors(ICIs) targeting the PD-1/PD-L1 pathway have shown significant efficacy in the treatment of solid tumors. However, approximately 60%-70% of patients do not benefit due to drug resistance or immune-related adverse events(irAEs), and the heterogeneity of the tumor microenvironment(TME) further limits their effectiveness. Single-target blockade strategies are insufficient to comprehensively reverse immune escape, which highlights the urgent need for multidimensional interventions. Numerous studies have shown that various TCM active ingredients and compounds can regulate the PD-1/PD-L1 pathway through multiple targets to enhance immune responses. Their mechanisms involve modulating key signaling pathways, mediating epigenetic changes, reprogramming cellular metabolism, and reshaping the immunosuppressive microenvironment. Therefore, this review, focusing on the PD-1/PD-L1 pathway, systematically summarized the research progress on TCM active ingredients, compounds, and patent medicines in cancer immunotherapy. It aims to analyze their immunoregulatory networks, providing theoretical insights and translational directions for optimizing cancer immunotherapy strategies.

Bufonis Venenum, the dried secretory product from the postauricular and cutaneous glands of Bufonidae, exerts antitumor activity primarily through bufadienolides. This review systematically summarizes the molecular mechanisms of key bufadienolides, including cinobufagin, bufalin, resibufogenin, bufotalin, arenobufagin, gamabufotalin, and cinobufotalin, in the treatment of malignant tumors over the past five years. Current evidence demonstrates that these compounds exert broad-spectrum antitumor effects through multi-target and multi-pathway modulation. In inhibiting tumor cell proliferation, these compounds primarily regulate signaling pathways such as mitogen-activated protein kinase(MAPK), phosphatidylinositol-3-kinase/protein kinase B(PI3K/AKT), and signal transducer and activator of transcription 3(STAT3). In inducing cell death, they eliminate malignant cells through multiple modalities including mitochondrion-mediated apoptosis, ferroptosis, and autophagy. In suppressing invasion and metastasis, they modulate epithelial-mesenchymal transition(EMT), matrix metalloproteinase(MMP) expression, and macrophage polarization within the tumor microenvironment. Furthermore, these compounds inhibit angiogenesis, enhance chemosensitivity, activate antitumor immune responses, and regulate epigenetic modifications. Combination therapy studies reveal that bufadienolides exhibit synergistic efficacy when being combined with clinical chemotherapeutic agents, and TCM preparations containing these compounds demonstrate antitumor properties through multi-target regulation. This review elucidates the antitumor molecular mechanisms of bufadienolides, aiming to provide a theoretical basis for further mechanism investigation and clinical translation.

Despite the widespread adoption of 5-fluorouracil (5-FU)-based regimens as first-line therapy for gastric cancer, a substantial number of patients develop innate or acquired resistance, highlighting the critical need to identify its underlying molecular drivers. RPRD1B (CREPT), a gene frequently overexpressed in GC, has been clinically associated with advanced tumor stage and poor prognosis. Functionally, RPRD1B promotes aggressive tumorigenic phenotypes by accelerating cell-cycle progression, potentiating proliferative signaling, and enhancing the migratory and invasive capacities of cancer cells. However, its functional role in mediating chemotherapy resistance has not been elucidated.

Tumour necrosis factor (TNF) is a pleiotropic cytokine originally identified for its ability to kill cancer cells. However, a paradoxical tumour-promoting role for TNF emerged when early attempts to exploit its anti-tumour activity in cancer therapy produced conflicting outcomes, raising the question of whether TNF should be viewed as a therapeutic agent or a treatment target in cancer. Here, we demonstrate that expression of cFLIP, a catalytically inactive paralogue of caspase-8 (CASP8), determines the susceptibility of melanoma cells to TNF and thereby controls melanoma growth in a syngeneic, immune-competent mouse model of B16F10 cutaneous melanoma. B16F10 melanoma cells lacking cFLIP (cFlipKO/KO cells) failed to grow in wild-type mice, whereas in TNF-deficient mice, cFlipKO/KO melanoma cells formed palpable tumours and exhibited robust subcutaneous growth. These findings indicate that TNF alone is sufficient to control melanoma growth in the absence of cFLIP. Importantly, the anti-tumour activity of TNF has predominantly been investigated through targeting cellular inhibitors of apoptosis proteins (cIAPs), which promotes RIPK1 activation and TNF-induced cytotoxicity. We show that genomic ablation of cIAPs or RIPK1, in contrast to cFLIP, neither triggered TNF-induced toxicity nor affected melanoma growth in vivo. Collectively, our data underscore the central role of cFLIP in regulating melanoma responses to TNF and suggest that endogenous immune surveillance as well as immunotherapies involving TNF could strongly benefit from cFLIP targeting strategies.

Glioblastoma is the most aggressive primary brain tumor in adults. Resistance of glioblastoma to the standard chemotherapy agent temozolomide (TMZ) correlates with the expression of the DNA repair enzyme O6-Methylguanine-DNA methyltransferase (MGMT). Additionally, tumor initiation and recurrence are associated with a subpopulation of glioblastoma stem cells (GSCs) which exhibit self-renewal properties, multipotency, and resistance to both chemotherapy and radiotherapy. To identify novel molecular biomarkers and therapeutic targets, we investigated the possible role of the oncoprotein Golgi phosphoprotein 3 (GOLPH3) in glioblastoma. GOLPH3 is overexpressed in many solid tumors and confers resistance to DNA-damaging chemotherapeutic agents. Its overexpression is also associated with poor prognosis in a variety of cancers, including glioblastoma. Here, we show that GOLPH3 knockdown in U87MG glioblastoma cells inhibits cell proliferation, promotes senescence and induces striking cellular and molecular changes toward a neuron-like phenotype. We analyzed the constitutive expression of GOLPH3, MGMT and mechanistic target of rapamycin (mTOR) signaling proteins in U87MG cells and in three GSCs representative of the three glioblastoma molecular subtypes. Our results suggest that these glioblastoma cell models may exhibit distinct responses to mTOR inhibition and TMZ. Finally, we show that GOLPH3 depletion reduces the activity of both mTOR complex 1 and 2 leading to decreased phosphorylation of their respective downstream targets S6K and Akt in both U87MG cells and the BT379 GSCs subtype. Our findings identify a potential therapeutic vulnerability that can be exploited to develop patient-tailored treatments in glioblastoma.

Simultaneous imaging of multiple intracellular RNA biomarkers is essential for precise molecular subtyping of cancers, but achieving orthogonal signal amplification with a low background remains a challenge. Herein, we design an entropy-driven palindromic DNA nanostructure by integrating four orthogonal catalytic circuits into a single nanostructure for accurate discrimination of different breast cancer cell subtypes based on multiplexed imaging of miRNA-21, miRNA-373, miRNA-155, and MnSOD mRNA. This system is constructed from two cruciform modules. Cruciform module 1 is formed by four substrate complexes with each consisting of a quencher-labeled template, a fluorophore-labeled reporter (Alexa Fluor 405, 488, 568, and 647) and an assistant strand carrying a palindromic arm for co-localizing the fluorophores and quenchers to suppress fluorescence. Cruciform module 2 is assembled from four fuel strands sharing the same palindromic sequence. Hybridization of two modules via their complementary palindromic arms generates self-assembled palindromic DNA nanostructure (SAPDN). Upon cellular internalization of SAPDN, each target RNA binds a specific toehold on its corresponding substrate complex to trigger an entropy-driven strand-displacement cascade, releasing a target-probe intermediate. Subsequent invasion by the fuel strand results in the liberation of intact target, the displacement of reporter strand, and the separation of fluorophore from the quencher to restore fluorescence. The liberated RNA targets can activate new substrate complexes to achieve catalytic signal amplification. By mapping the four fluorescence signatures inside living cells, the SAPDN platform can effectively differentiate different breast cancer subtypes, holding great promise in advanced molecular diagnostics.

Lipid metabolic reprogramming is a hallmark of cancer, in which fatty acid synthesis is crucial for the rapid proliferation and metastasis of cancer cells. The p53-R280K mutation drives aggressive cancer, yet its role in fatty acid synthesis remains unclear.

Acute lymphoblastic leukemia is the most common pediatric hematological disease representing less than 1% of hematological diseases in adults. The prognosis of ALL improved significantly in the last decades. Almost all patients require a therapy at the time of diagnosis. Rare cases of spontaneous remission of ALL have been described. We report a case of B-ALL that underwent spontaneous remission after an episode of infection and describe the cytogenetic changes associated with this uncommon clinical presentation of B-ALL.

Pancreatic cancer (PC) is a highly lethal malignancy. 4-10% are linked to inherited mutations in genes such as BRCA1/2, PALB2, ATM and mismatch repair (MMR) genes. Germline testing is essential to guide treatment decisions, yet delays remain common. Genetic testing models without pre-test assessment in a Hereditary Cancer Unit (HCU), have emerged as a strategy to improve earlier clinical decision-making. A retrospective, observational and descriptive study was conducted on 223 PC patients (55% male; average age 64 years) who underwent rapid germline genetic testing at Hospital General Universitario Gregorio Marañón (Madrid, Spain) between April 2019 and May 2024. Tests were ordered by oncologists with brief pre-test counseling, followed by a nurse-facilitated consent and peripheral blood collection. Post-test counseling in an HCU was offered for patients with variants of unknown significance (VUS) and pathogenic/likely pathogenic variants (PV), or upon physician or patient request. PV and VUS were identified in 32 (14.3%) and 82 (36.7%) patients, respectively. 50% of PV carriers did not meet familial PC criteria. Actionable mutations were detected in 14 (43.7%) of PV carriers, involving BRCA2 (6/32), PALB2 (1/32) and ATM (7/32). Treatment modifications occurred in 7/223 patients (3%), including PARP inhibitors or platinum-based regimens. Median time from the genetic test request to the results was 48 days (95% CI, 44-52). Mainstream genetic testing in PC is a viable approach to expedite results and facilitate precision oncology. Further studies are needed to evaluate long-term outcomes, cost-effectiveness and the psychosocial impact compared to traditional genetic counseling pathways.

Lactylation, a unique post-translational alteration, has been identified as an important epigenetic regulator of cancer metabolism, immune evasion, and treatment resistance. Recent research reveals that ultrasound-based biophysical stimulation may change tumor microenvironmental variables that affect lactate metabolism and subsequent lactylation processes. The purpose of this study was to better understand the predictive significance of lactylation-associated genes in lung adenocarcinoma (LUAD) and how they could interact with ultrasound-mediated treatment response.

In recent years, the clinical relevance of tertiary lymphoid structures (TLS) in cancer has become increasingly clear. However, the mechanisms that promote TLS development have remained obscure, largely because of a lack of animal models in which cause and effect studies can be performed. In this study, we used a mouse model in which TLS develop spontaneously in intraperitoneal tumors to address this issue.

Breast cancer (BC) is one of the most common and deadly cancers affecting women worldwide. This study is aimed at investigating the association between BC risk and two single nucleotide polymorphisms (SNPs): ESR1 (rs2234693) and PIK3CA (rs6443624) in a Bangladeshi population. A case-control study was conducted with 112 BC patients and 124 healthy controls (HCs). Genomic DNA was extracted from peripheral blood samples, and genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Genotype and allele frequencies were analyzed to assess their association with BC risk. Genotype distributions for both ESR1 and PIK3CA conformed to Hardy-Weinberg equilibrium. The CT genotype of ESR1 was associated with a reduced risk of BC, whereas the CA genotype of PIK3CA was linked to an increased risk. The dominant model for ESR1 (CT + TT vs. CC) demonstrated a significant protective effect (aOR = 0.288, 95% CI: 0.160-0.516), whereas the dominant model for PIK3CA (CA + CC vs. AA) showed a higher risk (aOR = 4.166, 95% CI: 2.363-7.347). Over-dominant models supported these findings, while recessive models for both SNPs showed no significant associations. The findings suggest that ESR1 (rs2234693) may have a protective role and PIK3CA (rs6443624) may increase susceptibility to BC in Bangladeshi women. These SNPs may provide preliminary evidence for potential use as genetic susceptibility markers, but larger multicenter studies are needed before any clinical application can be considered.

The functional plasticity of tumor-associated macrophages (TAMs) is a critical determinant of the immunosuppressive microenvironment in cervical cancer, yet its integration into actionable prognostic frameworks remains limited. This study aimed to establish a TAM polarization-centered model and elucidate the mechanisms of underlying tumor-immune crosstalk.

Differentiating neoplastic proliferation from inflammatory fibrosis in peripheral nerve hypertrophy is critical. We report a patient with a neurofibromatosis type 1 (NF1) deletion exhibiting extreme diffuse nerve enlargement and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)-like autoimmunity. This study aims to elucidate the underlying endoneurial fibrotic mechanism, specifically focusing on the signaling networks between Schwann cells (SCs) and fibroblasts.

Patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma who develop resistance to first-generation tyrosine kinase inhibitors (TKIs) without a T790M mutation face a therapeutic dilemma with limited and suboptimal options.