Expanding the chemical space of natural products is an effective strategy for discovering new drug candidates and has achieved remarkable results in activity screening. To efficiently explore the chemical space of nitidine, we developed a one-pot method to synthesize functionalized phenanthridines using commercially available or easily prepared aldehydes. Assisted by pyrrolidine and photocatalysts, the reaction proceeded under visible light at room temperature with satisfactory yields. Activity screening identified derivative e24, which reduced tumor cell PD-L1 expression more effectively than positive control JQ-1, while the prototype nitidine had minimal effects. Critically, e24 specifically targets CSN5, an essential regulatory factor, to induce PD-L1 degradation, thereby blocking the PD-1/PD-L1 interaction between T cells and tumor cells and activating the tumor immune microenvironment. In Lewis tumor and MC38 mice models, e24 exerted antitumor effects by enhancing tumor-infiltrating T-cell immunity and inhibiting the activation of immunosuppressive MDSCs and Tregs.

One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell-mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non-ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I-mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient-derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy.

Inflammatory bowel disease (IBD) comprises Crohn’s disease and ulcerative colitis, and that is a major risk factor for colitis-associated colorectal cancer (CAC), a distinct and aggressive malignancy driven by chronic intestinal inflammation. Artemisinins, a group of sesquiterpene lactones derived from Artemisia annua, have emerged as promising therapeutic candidates for IBD due to their potent anti-inflammatory and anticancer properties. In this review, we summarize the current evidence that artemisinins exert diverse pharmacological actions including modulation of immune responses, reduction of oxidative stress, preservation of epithelial barrier function, and suppression of oncogenic signaling relevant to IBD and CAC. We also introduce the recent progress in formulation strategies designed to enhance the bioavailability, tissue specificity, and therapeutic efficacy of artemisinin-based agents. By bridging traditional medical philosophy with modern pharmacological insights, artemisinins represent a versatile platform for preventing and treating inflammation-driven colorectal cancer. This review offers a comprehensive overview of their translational potential in addressing the IBD-CAC continuum.

Programmed cell death 1 ligand 1-targeted (PD-L1-targeted) immune checkpoint inhibitors are revolutionizing cancer therapy. However, strategies to induce endogenous PD-L1 degradation represent an emerging therapeutic paradigm. Here, we identified proanthocyanidins (PC) as a potent inducer of PD-L1 degradation through an endoplasmic reticulum-associated degradation (ERAD) mechanism. Mechanistically, PC exerted dual effects: First, it targeted and stabilized LKB1 to activate AMPK in tumor cells, subsequently inducing the phosphorylation of PD-L1 at Ser195 - a disruption that in turn impaired glycosylation of PD-L1 and promoted its retention in the ER. Second, PC directly bound to the E3 ubiquitin ligase SYVN1 to increase its protein stability, which strengthened PD-L1-SYVN1 binding, thereby accelerating K48-linked ubiquitination and proteasomal degradation of ER-retained PD-L1. This cascade culminated in the activation of CD8+ T cell-dominated antitumor immune responses, accompanied by suppression of myeloid-derived suppressor cells and regulatory T cells. In preclinical models of lung and colorectal cancer, PC exhibited synergistic antitumor efficacy when combined with anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA-4) antibodies. Notably, PC also potently inhibited the progression of azoxymethane/dextran sodium sulfate-induced orthotopic colorectal cancer in mice. Collectively, our findings unveil an antitumor mechanism of PC, establishing this small-molecule compound as an ERAD pathway-exploiting immune checkpoint modulator with promising translational potential for cancer therapy.

Background Immunotherapy targeting the PD-1/PD-L1 axis shows promise in colon and lung cancer treatment but faces challenges like high costs, low response rates, and drug resistance. Developing new small molecule inhibitors is complex. Repurposing existing drugs offers advantages, and paroxetine (PAR), an FDA approved antidepressant, has shown potential antitumor effects, yet its role as an immune checkpoint inhibitor is unclear. Methods In this study, we investigated PAR as an immune checkpoint inhibitor. We used various cell lines, including colon and lung cancer cells, and in vivo mouse models. Techniques such as Western blotting, flow cytometry, immunofluorescence, and immunohistochemistry were employed to analyze protein expression, cell surface marker levels, and immune cell populations. We also conducted gene knockdown and overexpression experiments, as well as molecular docking and binding assays. Results PAR downregulates PD-L1 protein levels in a concentration and time dependent manner in multiple cancer cell lines. In vivo, it inhibits tumor growth in colon and lung cancer mouse models by activating T cell immunity. Mechanistically, PAR binds to the Asp130 site of speckle-type POZ protein (SPOP), stabilizing this E3 ubiquitin ligase to promote PD-L1 ubiquitination and proteasomal degradation. Moreover, PAR combines with an anti-CTLA4 antibody enhances cancer cell inhibition, and it also suppresses AOM/DSS induced colon cancer. Conclusions Our findings demonstrate that PAR can function as an immune checkpoint inhibitor by targeting SPOP to degrade PD-L1, enhancing antitumor immunity. This provides a new theoretical basis for using PAR in colorectal and lung cancer treatment and offers insights into repurposing other drugs for cancer therapy.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Ferroptosis, an iron-dependent form of regulated cell death, represents a promising therapeutic strategy, but the clinical application of existing inducers is limited by systemic toxicity. Baicalin (BA), a natural flavonoid known to modulate mitochondrial function, emerges as a candidate to trigger ferroptosis via mitochondrial dysregulation. In this study, we demonstrate that BA potently induces ferroptosis in CRC cells and xenograft models, as evidenced by lipid peroxidation, glutathione depletion, and downregulation of GPX4. Mechanistically, quantitative proteomics identified the mitochondrial iron transporter SLC25A28 as the key target of BA. BA upregulates SLC25A28, which then specifically suppresses UQCRC2, a core subunit of the electron transport chain (ETC) Complex III. This SLC25A28-UQCRC2 axis disrupts mitochondrial respiration, leading to reactive oxygen species accumulation and, in concert with SLC25A28-mediated iron overload, synergistically triggers ferroptotic death. The causal role of this axis was confirmed by genetic rescue and pharmacological inhibition. Knockdown of UQCRC2 exacerbated BA-induced ferroptosis, while its overexpression conferred protection. Critically, BA’s antitumor effects were dependent on both SLC25A28 and ferroptosis, as genetic ablation of SLC25A28 or pharmacological inhibition of ferroptosis attenuated its efficacy in vivo. Furthermore, a ferroptosis-related gene signature predicted patient prognosis, underscoring the clinical relevance of this pathway. Our findings reveal the SLC25A28-UQCRC2-ETC axis as a novel, druggable mechanism for BA-induced ferroptosis, positioning BA as a promising mitochondria-targeting agent for CRC therapy.

Ferroptosis induced by ferrous ions (Fe2+) and lipid peroxidation accumulation is a novel form of regulated cell death that has become a hot topic in tumor therapy research. Identifying small-molecule drugs that can induce ferroptosis in tumor cells is a very attractive therapeutic strategy. Here, we screened a natural product, acevaltrate (ACE), which rapidly and strongly induces ferroptosis in colorectal cancer cells. ACE not only increases Fe2+ levels in colorectal cancer cells by targeting iron chaperones PCBP1/2 and reducing their expression but also disrupts the antioxidant system of colorectal cancer cells by targeting GPX4 and inhibiting its enzymatic activity, leading to its ubiquitin-mediated degradation. This dual effect of ACE makes it significantly more effective than classical ferroptosis inducers in inducing ferroptosis. Our animal experiments revealed that the therapeutic effect of ACE surpasses that of established ferroptosis-inducing drugs and is superior to that of first-line clinical drugs such as capecitabine and TAS-102. Importantly, ACE also demonstrated superior inhibitory effects in colorectal tumor organoids versus at the cellular level, underscoring its potential for clinical application. This study pioneers the discovery of a small molecule inhibitor that targets both PCBP1/2 and GPX4, offering a novel therapeutic strategy for eliminating cancer cells through ferroptosis.

Immune checkpoint inhibitors (ICIs) have shown limited efficacy in colorectal cancer (CRC). Chinese yam polysaccharide (CYP), a naturally derived plant polysaccharide, demonstrates immunomodulatory and antitumour activities. This study investigated whether CYP enhances the antitumour effects of αPD-1 monoclonal antibody (mAb) by modulating gut microbiota and metabolites. In MC38 and CT26 xenograft models, CYP synergistically inhibited tumour growth when combined with αPD-1 mAb. 16S rRNA sequencing revealed that the combination therapy enriched beneficial bacteria (such as Clostridia_UCG-014 and Actinobacteria) while reducing pathogenic bacteria (including Enterorhabdus and Desulfovibrionaceae). Antibiotic-mediated gut microbiota ablation abolished therapeutic benefits, confirming microbiota-dependent mechanisms. Cytometry by Time-Of-Flight indicated that the combination therapy reshaped the tumour microenvironment by inhibiting immunosuppressive M2 macrophages (CD206+ subset) and enhancing infiltration of cytotoxic CD8+ T cells. Metabolomics analysis demonstrated that the combination therapy effectively rectified tumour-induced metabolic dysregulation, particularly in pathways related to linoleic acid, tryptophan, and purine metabolism. Significantly, the purine-associated metabolite deoxyguanosine was identified to promote M2 macrophage polarization and tumour progression in vitro, whereas its levels were markedly attenuated following combined therapeutic intervention. The results suggest that CYP enhances the efficacy of αPD-1 mAb through remodeling gut microbiota, reducing pro-tumour metabolite (deoxyguanosine), and reprogramming the tumour immune microenvironment. This provides a novel strategy for enhancing CRC patients' response to anti-PD-1 immunotherapy response.

Immune checkpoint blockade has become an effective strategy for inhibiting tumor growth, especially immune checkpoint inhibitors that target the programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway, which have shown significant effects in tumor immunotherapy. In this study, we found that naturally sourced Cordyceps militaris extract can effectively downregulate the protein expression level of PD-L1 in human colorectal cancer cell lines. Further systematic isolation, purification, and analysis of its active components revealed that cordycepin (COR) is the key active molecule mediating PD-L1 degradation. Mechanistically, COR specifically and selectively targets the ubiquitin E3 ligase HMG-CoA reductase degradation protein 1, thus promoting the degradation of PD-L1 protein through the ubiquitin-proteasome pathway. This process significantly enhances the cytotoxic killing effect of effector T lymphocytes against colorectal cancer cells, ultimately achieving robust antitumor effects. Furthermore, this study also revealed that COR exhibits potential synergistic therapeutic effects when combined with anti-CTLA4 antibodies in preclinical tumor treatment. In summary, COR, as the primary bioactive component of Cordyceps militaris, demonstrates considerable potential to act as a small-molecule immune checkpoint modulator and inhibitor, thereby providing a novel therapeutic strategy for the immunotherapy of colorectal cancer.

Background Uric acid (UA) is the terminal product of purine metabolism. Elevated serum uric acid (SUA) levels, resulting from excessive synthesis or impaired excretion, are link to chronic inflammatory stress and increased risks of colorectal, breast, and prostate cancers. Hyperuricemia triggers a cascade of proinflammatory and oxidative responses, establishing a microenvironment conducive to tumorigenesis. Aim of review This review synthesizes evidence on how hyperuricemia drive inflammation and cancer transformation from global foundational research and clinical practice, elucidate UA metabolism as potential therapeutic strategy for inflammation-associated malignancies. Key scientific concepts of review Hyperuricemia-induced oxidative stress, DNA damage and genomic instability, while simultaneously activating proinflammatory signaling pathways. These interconnected pathways establish a persistent, proinflammatory microenvironment that fosters the transition from inflammation to cancer. Therapeutic strategies targeting UA metabolism (including pharmacologic interventions and dietary modifications) may mitigate chronic low-grade inflammation and reduce the cancer risk associated with hyperuricemia. Dysregulated UA metabolism emerges as a critical modulator linking chronic inflammation with oncogenesis.

BACKGROUND:The incidence of inflammatory bowel disease (IBD) continues to increase annually, accounting for about 6.8 million cases in 2017 worldwide. However, there is currently no gold standard for the diagnosis of IBD.METHODS:A method for the detection of four microorganisms in feces by two-dimensional polymerase chain reaction (2D-PCR) has been developed. Plasmids were used to validate the sensitivity and specificity of the method. Clinical samples were tested using a 2D-PCR method. Optimal diagnostic thresholds for IBD were determined based on ROC results.RESULTS:Of the 112 samples, 78 were from IBD patients and 34 from patients with other gastrointestinal (GI) diseases. Thomasclavelia ramosum and univ907-1062 positivity are necessary, and two or more positives of the three bacteria (Thomasclavelia spiroforme, Thomasclavelia saccharogumia or Clostridium cluster XVIII) are the optimal diagnostic thresholds for IBD. The area under the curve was 0.826 with a 95% confidence interval of 0.735-0.981 and a p-value of 0.000, corresponding to a sensitivity of 0.769 and a specificity of 0.853.CONCLUSIONS:Based on the detection results of microorganisms, IBD and GI can be effectively distinguished. The detection of four microorganisms in feces can assist clinicians in the differential diagnosis of IBD. Our experiment aims to provide a better program for early clinical diagnosis and regular dynamic monitoring of IBD.

Severe immunosuppression is a hallmark of colorectal cancer (CRC). Myeloid-derived suppressor cells (MDSCs), one of the most abundant components of the tumor stroma, play an important role in the invasion, metastasis, and immune escape of CRC. MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells, including T and natural killer cells, as well as by inducing the proliferation of immunosuppressive cells, such as regulatory T cells and tumor-associated macrophages, which, in turn, promote the growth of cancer cells. Thus, MDSCs are key contributors to the emergence of an immunosuppressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity. In this narrative review, we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment, the current therapeutic approaches and technologies targeting MDSCs, and the therapeutic potential of modulating MDSCs in CRC treatment. This study provides ideas and methods to enhance survival rates in patients with CRC.

Colorectal cancer (CRC) development involves a series of molecular events that drive the progression from normal colorectal epithelium to adenoma and eventually to invasive carcinoma. While the involvement of extrachromosomal circular DNAs (ecDNAs) in cancer genome remodeling has been established, their specific roles in CRC formation remain unclear. Using Circle-Sequencing and whole transcriptomic sequencing, we comprehensively profile circular DNAs and transcriptomes in healthy individuals, colorectal adenoma, and CRC patients. Our delineate analyses characterize the key circular DNAs involved in oncogene expression through the normal-adenoma-carcinoma continuum and highlight that immune response-related pathways and cell cycle pathways, are the dominat events in CRC progression. Notably, chr8 ecDNA 64950741-114379093 exhibits robust up-regulation during CRC progression. Further validation in a new cohort of 50 CRC patients confirms the higher expression of chr8 ecDNA 64950741-114379093 and its strong correlation with poor prognosis. Thus, these findings provide unprecedented insights into the landscape of circular DNAs in CRC and highlights the potential of chr8 ecDNA 64950741-114379093 as a promising biomarker and therapeutic target for CRC management.

Immune checkpoint inhibitors (ICIs) are drugs that inhibit immune checkpoint (ICP) molecules to restore the antitumor activity of immune cells and eliminate tumor cells. Due to the limitations and certain side effects of current ICIs, such as programmed death protein-1, programmed cell death-ligand 1, and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) antibodies, there is an urgent need to find new drugs with ICP inhibitory effects. In this study, a network-based computational framework called multi-network algorithm-driven drug repositioning targeting ICP (Mnet-DRI) is developed to accurately repurpose novel ICIs from ≈3000 Food and Drug Administration-approved or investigational drugs. By applying Mnet-DRI to PD-L1, maprotiline (MAP), an antidepressant drug is repurposed, as a potential PD-L1 modifier for colorectal and lung cancers. Experimental validation revealed that MAP reduced PD-L1 expression by targeting E3 ubiquitin ligase speckle-type zinc finger structural protein (SPOP), and the combination of MAP and anti-CTLA4 in vivo significantly enhanced the antitumor effect, providing a new alternative for the clinical treatment of colorectal and lung cancer.

Promoting tumor cell senescence arrests the cell cycle of tumor cells and activates the immune system to eliminate these senescent cells, thereby suppressing tumor growth. Nevertheless, PD-L1 positive senescent tumor cells resist immune clearance and possess the ability to secret various cytokines and inflammatory factors that stimulate the growth of tumor cells. Consequently, drugs capable of both triggering senescence in tumor cells and concurrently diminishing the expression of PD-L1 to counteract immune evasion are urgently needed. Here, a berberine derivative B68 is developed, which specifically induces tumor cell senescence by targeting BMI1. B68 also involves the degradation of PD-L1 by targeting CSN5, thereby disrupting the immunosuppressive PD-1/PD-L1 interaction and enabling rapid clearance of senescent tumor cells. This approach simultaneously inhibits tumor progression and activates T cell immunity, as evidenced by the robust antitumor response following B68-induced immunization of senescent cancer cells. Moreover, the synergistic effect of B68 with anti-CTLA4 therapy further enhances antitumor immunity, and its ability to induce senescence in cancer cells triggers a strong protective response by dendritic and CD8+ T cells. These findings provide a scientific basis for developing a new tumor treatment strategy based on senescence induction and lay the foundation for further preclinical research.

Ethnopharmacological relevanceTraditional Chinese medicine (TCM) has been used for centuries to treat various types of inflammation and tumors of the digestive system. Portulaca oleracea L. (POL), has been used in TCM for thousands of years. The chemical composition of POL is variable and includes flavonoids, alkaloids, terpenoids and organic acids and other classes of natural compounds. Many of these compounds exhibit powerful anti-inflammatory and anti-cancer-transforming effects in the digestive system.Aim of studyIn this review, we focus on the potential therapeutic role of POL in NASH, gastritis and colitis and their associated cancers, with a focus on the pharmacological properties and potential mechanisms of action of the main natural active compounds in POL.MethodsThe information and data on Portulaca oleracea L. and its main active ingredients were collated from various resources like ethnobotanical textbooks and literature databases such as CNKI, VIP (Chinese literature), PubMed, Science Direct, Elsevier and Google Scholar (English literatures), Wiley, Springer, Tailor and Francis, Scopus, Inflibnet.ResultsKaempferol, luteolin, myricetin, quercetin, genistein, EPA, DHA, and melatonin were found to improve NASH and NASH-HCC, while kaempferol, apigenin, luteolin, and quercetin played a therapeutic role in gastritis and gastric cancer. Apigenin, luteolin, myricetin, quercetin, genistein, lupeol, vitamin C and melatonin were found to have therapeutic effects in the treatment of colitis and its associated cancers. The discovery of the beneficial effects of these natural active compounds in POL supports the idea that POL could be a promising novel candidate for the treatment and prevention of inflammation-related cancers of the digestive system.ConclusionThe discovery of the beneficial effects of these natural active compounds in POL supports the idea that POL could be a promising novel candidate for the treatment and prevention of inflammation-related cancers of the digestive system. However, clinical data describing the mode of action of the naturally active compounds of POL are still lacking. In addition, pharmacokinetic data for POL compounds, such as changes in drug dose and absorption rates, cannot be extrapolated from animal models and need to be measured in patients in clinical trials. On the one hand, a systematic meta-analysis of the existing publications on TCM containing POL still needs to be carried out. On the other hand, studies on the hepatic and renal toxicity of POL are also needed. Additionally, well-designed preclinical and clinical studies to validate the therapeutic effects of TCM need to be performed, thus hopefully providing a basis for the validation of the clinical benefits of POL.