Search Results (7,577)

The hepatocyte growth factor (HGF)/c-Met signaling pathway plays a central role in cellular proliferation, survival, migration, invasion, angiogenesis, and therapeutic resistance. Aberrant c-Met activation, driven by gene amplification, overexpression, activating mutations, exon 14-skipping alterations, or ligand-dependent stimulation, drives the development and progression of many solid tumors, positioning c-Met as a key target for anticancer drug development. The clinical effectiveness of c-Met-targeted treatments such as crizotinib, capmatinib, tepotinib, savolitinib, and cabozantinib has confirmed c-Met as a viable oncogenic driver for therapy, leading to the development of various next-generation inhibitors with different structures. This review provides a comprehensive perspective on small-molecule c-Met inhibitors from the perspectives of medicinal chemistry and structure-based drug design, encompassing approved drugs, investigational agents, natural-product-inspired leads, and emerging multitarget anticancer therapeutics. Particular emphasis is given to the principles of molecular recognition that govern c-Met inhibition. This includes the structure of the kinase domain, interactions at the ATP-binding site, recognition of the hinge region, and the different binding modes of Type I, Type II, and allosteric inhibitors. The design, synthesis, biological evaluation, and structure–activity relationships of diverse heterocyclic scaffolds that have shaped c-Met inhibitor discovery are critically analyzed. Key medicinal chemistry strategies, including scaffold hopping, bioisosteric replacement, conformational optimization, molecular hybridization, and multitarget pharmacophore integration, are discussed in the context of potency, selectivity, resistance management, and drug-like properties. Particular attention is given to the integration of structural biology, molecular docking, binding-mode analysis, and structure-guided optimization approaches that have enabled the development of potent c-Met-directed inhibitors. In addition, recent advances in dual- and multitarget agents that simultaneously modulate c-Met and complementary therapeutic targets, including VEGFR-2, EGFR, AXL, MER, PARP1, CDK2, and tubulin, are highlighted as promising strategies for overcoming pathway redundancy and acquired resistance. This review summarizes contemporary structure-based and medicinal chemistry principles underlying c-Met inhibitor discovery, critically evaluates the relationship between biochemical potency and therapeutic efficacy, and provides a framework for the rational design of next-generation c-Met-targeted and multitarget anticancer agents. Full article

Epigenetic regulation through histone acetylation plays a critical role in gene expression and cancer progression. Because of its pivotal role in chromatin remodeling, Histone deacetylase 3 (HDAC3) has become a promising therapeutic target. In this study, an artificial intelligence (AI)-driven strategy was utilized to prioritize potential HDAC3 inhibitors among FDA-approved compounds to accelerate drug repurposing for cancer therapy. Existing HDAC3 inhibitors were identified in the BindingDB and were used to develop a machine learning (ML) model trained on the most potent inhibitors to identify molecular descriptor patterns associated with HDAC3 inhibition. The ML workflow then screened 1615 FDA-approved compounds, yielding 120 candidates with predicted HDAC3 inhibitory activity. Among these, known HDAC inhibitors, including romidepsin, vorinostat, and panobinostat, were selected, suggesting that the workflow can recover known HDAC inhibitors during virtual screening. Interestingly, tyrosine kinase inhibitors such as imatinib and osimertinib were also identified, indicating potential structural overlap between kinase- and HDAC3-binding pharmacophores. The analysis of the predicted docking scores also supported the prioritization results since the top 10 compounds had more negative predicted docking scores than the bottom 10 (p = 0.0074). This shows that the suggested workflow is useful for prioritizing FDA-approved compounds as potential HDAC3 inhibitors for further study. Full article

Neurotropic viruses have evolved sophisticated mechanisms to evade host immune responses within the central nervous system (CNS), enabling viral replication, persistence, latency, and neuropathogenesis while minimizing irreversible neuronal damage. Unlike peripheral tissues, the CNS requires tightly regulated antiviral immunity to balance effective pathogen control with the preservation of neural function. This review examines the diverse yet convergent immune evasion strategies employed by major neurotropic RNA and DNA viruses, including herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), rabies virus (RABV), flaviviruses, alphaviruses, enteroviruses, and JC virus (JCV). We discuss viral interference with innate immune sensing pathways, including RIG-I-like receptors (RLRs) and cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling, inhibition of type I interferon induction and Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling, modulation of interferon-stimulated effector mechanisms, and disruption of antigen presentation and adaptive immune surveillance. The review further highlights the distinct roles of viral latency, long-term persistence, neuronal–glial interactions, and metabolic reprogramming in facilitating prolonged infection within the CNS. Emerging evidence indicates that successful neurotropic viruses rarely achieve immune evasion through complete suppression of host defenses; instead, they fine-tune antiviral responses to preserve host cell viability while preventing viral clearance. Finally, we discuss current knowledge gaps and emphasize the need for advanced human-relevant models, single-cell and spatial multi-omics, and systems-level approaches to better define virus–host interactions within the CNS. A deeper understanding of these integrated immune evasion networks may reveal novel therapeutic strategies that enhance antiviral immunity while limiting neuroinflammation and preserving neurological function. Full article

Background: Ripretinib, a switch-control kinase inhibitor approved for advanced gastrointestinal stromal tumor (GIST), inhibits primary and secondary KIT and PDGFRA mutations. Real-world data from Western and Middle Eastern populations remain limited. We report outcomes from a molecularly characterized Israeli multicenter cohort. Methods: We conducted a multicenter retrospective cohort study across seven university-affiliated medical centers in Israel. Patients with advanced GIST receiving Ripretinib at any treatment line were eligible. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method, and response was assessed according to modified RECIST v1.1. Results: Sixteen patients were identified (median age, 67.5 years; 75.0% received Ripretinib in the fourth-line setting). KIT exon 11 mutations were present in 62.5% of patients, including five with secondary resistance mutations involving exon 13 or exons 17/18. Median PFS was 7.0 months (95% CI, 2.0–13.0) and median OS was 14.7 months (95% CI, 4.4–NR). Individual outcomes varied substantially, with PFS ranging from 2.0 to 60.2 months and OS from 2.2 to 60.2 months. Three patients achieved complete responses, with PFS of 20.0, 33.6, and 60.2 months. ORR was 56.3% (CR, n = 3; PR, n = 6) and DCR was 81.3%. No dose reductions or treatment discontinuations due to adverse events were documented; however, adverse events were recorded in only 4 of 16 patients. Conclusions: Ripretinib demonstrated clinical activity in this small, heavily pre-treated cohort. The relatively high ORR and wide variability in outcomes should be interpreted cautiously given the small sample size, retrospective design, and absence of central radiological review. Durable responses were observed in some patients with KIT exon 11 and secondary exon 17/18 mutations, but this exploratory observation does not establish a predictive molecular subgroup. Larger prospective studies with systematic molecular, radiological, and safety assessment are warranted. Full article

Colorectal cancer (CRC) has shown significant heterogeneity regarding its response to immunotherapy. Long-lasting, beneficial effects have been observed in mismatch repair-deficient, microsatellite instability-high (dMMR/MSI-H) tumours, while mismatch repair-proficient, microsatellite stable (pMMR/MSS) tumours have remained resistant. Such differences in results have been studied in this review through the “hot” and “cold” tumour concept. It explains how various biological and microenvironmental factors play a role in immune resistance and T-cell priming and infiltration. Key factors include a low neoantigen load and defects in antigen presentation, which reduce the overall immune recognition of tumour cells. The review also studies certain processes such as Wnt/β-catenin and mitogen-activated protein kinase (MAPK) signalling and what input they have in the prevention of effective antitumour immune responses. Conventional treatments like chemotherapy and radiotherapy have been considered alongside more targeted treatments such as the inhibition of vascular endothelial growth factor (VEGF) signalling and the suppression of myeloid-mediated immune evasion, to convert “cold” MSS tumours into immune-responsive lesions. Methods which aim to modify the tumour microenvironment such as metabolic reprogramming and microbiome modulation have also been covered in this review. Artificial intelligence and nanomedicine are new technologies that could provide improved patient stratification and therapeutic precision, although their clinical application in pMMR/MSS CRC remains under investigation. A systematic literature search of PubMed and PubMed Central (PMC) was conducted from 10 June 2026 to 19 August 2026 using predefined eligibility criteria, with study selection reported according to PRISMA 2020. Because of substantial heterogeneity in study design, therapeutic approach and reported outcomes, the included evidence was synthesized narratively rather than by meta-analysis. A total of 158 studies were included. Full article

Background/Objectives: Sjögren’s Syndrome (SS) is an autoimmune disorder with impaired exocrine gland function. Its pathogenesis remains elusive, but aberrant innate/adaptive immunity and dysregulated interferon signaling are core features. Current SS research lacks exploration of innate immune mechanisms and therapeutic targets. Phloretin, a natural dihydrochalcone derivative, inhibits excessive innate immune activation, yet its role and mechanism in SS remain unreported. Methods: This study aimed to explore the therapeutic efficacy of phloretin against Sjögren’s syndrome (SS) and elucidate the regulatory mechanism underlying its effects on dendritic cells (DCs) and the Stimulator of Interferon Genes (STING)-driven innate immune cascade. Clinical specimens were utilized to analyze DC infiltration and STING expression in the labial glands of SS patients. In vivo experiments were conducted on NOD/Ltj SS mice with phloretin treatment, using hydroxychloroquine as a positive control. For in vitro studies, DCs were stimulated with poly I:C to verify the functional effects of phloretin and its regulatory role in the STING/TANK-binding kinase 1 (TBK1)/Interferon Regulatory Factor 3 (IRF3) signaling. Salivary secretion, glandular inflammatory responses, and systemic immune overactivation were evaluated in SS mice. In poly I:C-stimulated DCs, cell activation, migration, and co-stimulatory molecule expression were measured. The regulatory effects of phloretin on the STING signaling cascade and STING ubiquitin-mediated degradation were examined by Western blotting. Phloretin, initially identified as a candidate compound via virtual screening, was subjected to thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) and molecular dynamics simulation (MD) for direct binding verification with STING. The STING overexpression rescue experiment further corroborates that phloretin modulates innate immune responses in a STING-dependent manner. Results: Clinical results revealed obvious infiltration of CD11c⁺STING⁺ DCs and CD11c⁺p-TBK1⁺ DCs in labial gland lesions of SS patients. In NOD/Ltj SS mice, phloretin treatment recovered salivary secretion, relieved glandular inflammatory injury, and restrained excessive activation of innate and adaptive immune responses, showing comparable therapeutic effects compared with hydroxychloroquine. In vitro experiments confirmed that phloretin could alleviate poly I:C-induced abnormal activation and migration of DCs, as well as reduce the expression of co-stimulatory molecules. Mechanistically, phloretin was found to interfere with the STING signaling cascade, alter the ubiquitination level of STING protein, and further inhibit the abnormal activation of DCs, which may contribute to its protective effects against Sjögren’s syndrome. Notably, results from MD, CETSA and DARTS collectively validate the interaction between phloretin and STING protein, providing solid molecular-level evidence for its regulatory effect on STING signaling transduction. Conclusions: DCs and STING-driven innate immunity critically contribute to SS progression. Phloretin effectively ameliorates SS-related immune disorders by restraining DC overactivation and STING signaling, supporting it as a promising candidate agent for SS treatment. Full article

Acute lung injury (ALI) is a common clinical acute respiratory disorder driven primarily by a diffuse pulmonary inflammatory response. Cordycepin (COR) is a bioactive metabolite extracted from the fungus Cordyceps militaris, which possesses antioxidant and anti-inflammatory properties. However, its underlying molecular mechanism remains to be elucidated. This study evaluated the therapeutic effect of COR on ALI and the underlying molecular mechanisms. MH-S cells were primed with lipopolysaccharide (LPS) at 1 µg/mL for 24 h and then treated with varying doses of COR for an additional 24 h. WB and RT-qPCR analyses showed that COR inhibited the phosphorylation of TGF-β-activated kinase 1 (TAK1) as well as the key kinases in the MAPK and NF-κB pathways in LPS-induced MH-S cells, as evidenced by decreased TAK1, p38, JNK, IκB-α and P65 expression levels, as well as decreased TNF-α, IL-6, IL-1β, MAP3K7, MAPK8 and MAPK14 relative expression. Six-week-old BALB/c mice were intranasally instilled with LPS at 3 mg/kg, followed 24 h later by oral gavage administration of various concentrations of COR. The results showed that COR can effectively suppress the progression of pulmonary tissue injury; similarly, the expression levels of key proteins and inflammatory factors in the TAK1-MAPK and NF-κB signaling pathways were downregulated. In summary, COR exerts a therapeutic effect on ALI by directly targeting TAK1 to inhibit the activation of the MAPK and NF-κB signaling pathways and concurrently suppressing key inflammatory cytokines. Full article

Protein kinases are the most intensively targeted protein family for small-molecule drugs, and the large volume of inhibitory-assay data reported for them makes the family particularly well suited to data-driven and machine-learning approaches to drug discovery. This data, however, is scattered across heterogeneous assays, reports and publications, and its reuse for modeling requires substantial curation. Here, we present Kinoteca, a curated database of kinase inhibitory-activity data derived from ChEMBL and accessible through a web interface for browsing, filtering, visualization and download. Kinoteca reconciles the multiple raw independent measurements reported for each combination of compound, kinase and activity type into a single fused activity value, together with a dispersion score based on the mean unsigned error (MUE) that quantifies how consistent the underlying measurements were. The database currently organizes curated data for 585 kinases and arranges them along biologically meaningful groupings such as kinome family, pathway and source organism. Curated activities can be filtered by the physicochemical properties of the assayed molecules or by measurement quality, explored through summary statistics, activity distributions and structural clustering, and exported either as curated or semi-raw data tables or as molecular structure files. These data formats are suitable for the direct training of machine learning models, such as activity prediction models. By delivering reconciled, analysis-ready data with its provenance preserved, Kinoteca aims to lower the barrier to reproducible, data-driven kinase drug discovery. Full article

Eco-3, a microbial-derived daidzin, has been reported to possess diverse biological activities; however, its effects on osteoclast differentiation and the underlying molecular mechanisms remain unclear. In the present study, we investigated the effects of Eco-3 on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis and explored the signaling pathways involved using RAW264.7 macrophages. Eco-3 suppressed RANKL-induced osteoclast formation at the concentrations tested without significantly affecting cell viability. Eco-3 also altered F-actin organization and reduced the expression of key osteoclastogenic markers, including tartrate-resistant acid phosphatase (TRAP), nuclear factor of activated T cells c1 (NFATc1), c-Fos, and cathepsin K (CTSK). In particular, Eco-3 attenuated NFATc1 expression during the early stage of osteoclast differentiation, suggesting interference with the transcriptional program associated with osteoclastogenesis. Furthermore, RANKL stimulation progressively increased TANK-binding kinase 1 (TBK1) phosphorylation during osteoclast differentiation, whereas Eco-3 attenuated this activation. Genetic silencing of TBK1 suppressed osteoclast formation, while pharmacological inhibition of TBK1 reduced TBK1 phosphorylation, osteoclastogenic gene expression, and osteoclast formation. Collectively, these findings suggest that Eco-3 suppresses RANKL-induced osteoclastogenesis, at least in part, through modulation of the TBK1–NFATc1 signaling axis in RAW264.7 macrophages. Our findings identify TBK1 as a potential regulatory component of osteoclast differentiation and suggest that Eco-3 warrants further investigation as a potential bioactive candidate for osteoclast-related bone disorders. Full article

Melon (Cucumis melo L.) is a globally significant horticultural crop whose fruit quality and postharvest shelf life are profoundly influenced by oxidative stress. Abscisic acid (ABA)-responsive element binding factors (ABFs), which represent the Group A subfamily of the basic leucine zipper (bZIP) transcription factor family, serve as pivotal components in the ABA signaling pathway. These factors play essential roles in regulating plant responses to abiotic stress as well as fruit development and maturation processes. In this study, a total of nine CmABF gene family members (CmABF1–CmABF9) were successfully identified within the melon genome using genome-wide identification techniques. Bioinformatic analysis indicated that all CmABF proteins contain a conserved bZIP domain. Physicochemical property analysis revealed that most of these proteins are unstable hydrophilic proteins and all are localized to the cell nucleus. Phylogenetic analysis categorized the CmABF family into three distinct evolutionary branches (Groups A, B, and C), exhibiting high conservation with homologous genes in Arabidopsis thaliana, Solanum tuberosum, and other species. Promoter analysis demonstrated that CmABF genes are rich in hormone-responsive elements (such as abscisic acid-responsive element (ABRE) and gibberellin-responsive element (GARE)) and stress-responsive elements (such as MYB binding sites (MBS) and anaerobic-response element (ARE)). To investigate their responses to oxidative stress and ABA signaling, we analyzed the expression patterns of these genes in melon fruit at 0, 7, 14, 21, 28, and 35 days of postharvest storage under ozone (O₃, an oxidative stressor), exogenous abscisic acid (ABA), and the ABA synthesis inhibitor nordihydroguaiaretic acid (NDGA) using RNA-seq and qRT-PCR. The results showed that ozone treatment significantly induced the up-regulation of CmABF9 while inhibiting the early expression of CmABF2 and CmABF4. ABA treatment generally promoted the transcription of family members during the late stages of storage (35 d). NDGA treatment suppressed the expression of CmABF2 and CmABF4 during the early storage stage (7 d), while markedly increasing their expression levels at later storage stages (28 d and 35 d), suggesting a compensatory feedback response under endogenous ABA deficiency. Furthermore, protein–protein interaction predictions indicated potential close interactions between CmABF proteins and SnRK2 protein kinases. This study provides a theoretical basis for elucidating the molecular mechanisms of the CmABF family in regulating postharvest oxidative stress in melon and provides candidate gene resources for molecular breeding aimed at enhancing resistance and extending the shelf life of melon fruit. Full article

Fatty liver hemorrhagic syndrome (FLHS) is a prevalent metabolic disease in laying hens, causing severe economic losses. A previous study showed that conjugated linoleic acids (CLA) alleviated estrogen-induced FLHS in chickens, but the mechanism remains unclear. In the present study, we found that CLA improved serum lipid homeostasis, reduced hepatic lipid accumulation, and enhanced antioxidant activity in FLHS chickens. Transcriptome analysis identified differentially expressed genes enriched in inflammatory response, lipid homeostasis, carbohydrate metabolism, and mitogen-activated protein kinase (MAPK)/peroxisome proliferator-activated receptor (PPAR)/insulin signaling pathways. Metabolome analysis detected differentially abundant metabolites enriched in bile secretion, thyroid hormone synthesis, the insulin signaling pathway, and glycerophospholipid metabolism. Integrated analyses revealed that CLA reshaped the hepatic metabolic profile by upregulating protective metabolites (such as ubiquinol) and downregulating pro-inflammatory/lipogenic metabolites (such as 15-hydroperoxyeicosa-8Z,11Z,13E-trienoate), which synergized with key gene regulation (fatty acid synthase, jun proto-oncogene, and fatty acid desaturase 2) and core pathway activity (MAPK/nuclear factor kappa-B inhibition, PPARα activation). The multi-omics study using an estradiol-induced rooster FLHS model elucidated the molecular regulatory network of CLA against hepatic steatosis and liver injury, and provided preliminary mechanistic clues for developing CLA functional additives to prevent and treat FLHS in commercial laying hens. Full article

Background: Opioid use during pregnancy is linked to preterm birth, fetal growth restriction, and Neonatal Opioid Withdrawal Syndrome. While the placenta is the primary regulator of the uterine environment, the precise molecular mechanisms by which opioids dismantle placental function remain poorly defined. Methods: The transcriptomic landscape of opioid-exposed human placentas from a unique Hawai’i-based cohort was characterized. Results: Transcriptional signatures were defined by genes involved in translational inhibition and metabolic attenuation. Integrative network modeling predicted a prominent stress-signaling hub centered on p38 Mitogen-Activated Protein Kinase and Extracellular Signal-Related Kinase 1/2, paralleling a broad suppression of ribosomal protein transcripts (Ribosomal Protein 27S, -29, and -39). This response was further characterized by the inhibition of the Myelecytomatosis Proto-Oncogene regulatory hub, predicting a loss of mitochondrial phosphate transport through associated genes (via Solute Carrier Family 25A3) and cell-cycle progression (via S-Phase Kinase-Associated Protein 1). Additionally, the genes in this model suggested upregulation of antisense regulatory brakes, such as RAP2C Antisense RNA 1, which might further reinforce this inhibitory state. Conclusion: The findings suggest that prenatal opioid exposure is associated with the disruption of placental homeostasis. This may be coordinated by protein synthesis and bioenergetic flux, as inferred from the modeled eukaryotic Translation Initiation Factor-mediated Integrated Stress Response. These findings establish a localized, clinical baseline of human placental stress, highlighting candidate molecular regulatory nodes to guide future mechanistic studies and biomarker discovery in exposed pregnancies. Full article

High alkalinity, a major stress in saline–alkaline water, often leads to oxidative damage and apoptosis. Taurine has been shown to enhance the tolerance of aquatic animals to environmental stress, but whether it can reduce toxicity of alkalinity on Chinese mitten crab (Eriocheir sinensis) has not been determined. Thus, in this study, we investigated whether taurine could alleviate the deleterious effects of alkalinity stress on E. sinensis. The results revealed that taurine can improve the survival rate of the crab under 35.00 mmol/L alkalinity stress. Meanwhile, taurine inhibited the production of reactive oxygen species (ROS) and ameliorated the oxidative damage induced by alkalinity stress in crab. Taurine also inhibited alkalinity stress-mediated induction of mitogen-activated protein kinase-related pathways, subsequently suppressing the mRNA expression of Caspase 8 and Bax and preventing the occurrence of alkalinity stress-induced apoptosis in E. sinensis. In addition, inhibition of alkalinity stress-induced apoptosis by taurine may be related to the ability of taurine to bind to MAPK proteins. Overall, these results suggested that taurine can relieve the toxicity of high alkalinity on E. sinensis through mitigating oxidative damage and inhibiting apoptosis, supporting its applicability as a treatment for oxidative damage induced by high alkalinity. Full article

Diabetic retinopathy, diabetic kidney disease, and diabetic peripheral neuropathy remain major causes of visual loss, kidney failure, pain, disability, and reduced quality of life despite improvements in glycemic and cardiovascular risk management. Oxidative stress, mitochondrial dysfunction, iron dyshomeostasis, lipid peroxidation, and sterile inflammation are shared features of these complications and converge on regulated cell-death programs. Ferroptosis is driven by iron-dependent phospholipid peroxidation when glutathione peroxidase 4 and complementary antioxidant systems are insufficient, whereas pyroptosis is an inflammatory lytic process executed by gasdermins after activation of inflammasome-associated or other inflammatory caspases. Nuclear factor erythroid 2-related factor 2 (NRF2) connects these pathways by regulating glutathione synthesis, lipid peroxide detoxification, iron handling, mitochondrial homeostasis, and redox-sensitive inflammatory signaling. Dietary polyphenols may influence this network through electrophilic or kinase-dependent NRF2 activation, preservation of the SLC7A11-glutathione-GPX4 axis, modulation of iron and lipid metabolism, and inhibition of NF-kappaB, TXNIP, NLRP3, caspase-1, and gasdermin signaling. This integrative review critically examines mechanistic, preclinical, and human evidence for these effects in the diabetic retina, kidney, and peripheral nerve. The strongest direct preclinical evidence currently concerns corilagin, resveratrol, isoquercetin, quercetin, epigallocatechin gallate, punicalagin, and selected anthocyanin-rich or phenolic extracts. Human studies suggest possible benefits for albuminuria, retinal edema, endothelial function, and neuropathic outcomes, but they rarely measure ferroptosis- or pyroptosis-specific biomarkers and their results are heterogeneous. The proposed ferroptosis–pyroptosis–NRF2 network should therefore be viewed as a biologically plausible integrative framework rather than a clinically validated linear pathway. Future trials require chemically characterized interventions, exposure biomarkers, tissue-relevant pharmacokinetics, prespecified regulated-cell-death panels, and clinically meaningful microvascular endpoints. Full article

Bispecific antibodies (bsAbs) and bispecific antibody–drug conjugates (bsADCs) represent promising classes of emerging targeted therapeutics with the potential to overcome tumor heterogeneity and resistance in colorectal cancer (CRC). BsAbs can simultaneously engage multiple tumor antigens or immune cells or bind two distinct epitopes within a single target, enabling mechanisms of action beyond the capabilities of monoclonal antibodies. Bispecific T cell engagers facilitate targeted destruction of tumors through immune cell recruitment, while dual immune checkpoint inhibitors enhance immune activation by blocking T cell inhibitory signals. Furthermore, bsAbs can mediate dual signaling pathway inhibition through binding multiple receptor tyrosine kinase receptors or other tumor cell surface proteins. BsADCs integrate the dual-antigen recognition of bsAbs with targeted payload delivery, utilizing receptor-mediated endocytosis to deliver potent cytotoxic payloads selectively to CRC cells, while minimizing systemic toxicity. Recent advances in bsAb engineering, linker chemistry, site-specific conjugation, and payload design have accelerated the development of bsADCs for solid tumors, including CRC. BsAbs and bsADCs provide opportunities to improve tumor selectivity, enhance internalization, overcome antigen escape, and expand the population of CRC patients eligible for targeted therapy. Emerging preclinical studies demonstrate encouraging anti-tumor activity for bispecific modalities in CRC, while early clinical trials are beginning to establish their translational potential. This review summarizes the current landscape of bsAbs and bsADCs in therapeutic development for CRC, highlighting key biological targets, engineering strategies, mechanisms of action, and clinical status. We also discuss the major challenges facing clinical translation and provide perspectives on future directions for bispecific therapies in CRC. Full article